PHOENIX RISING

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 to produce new and 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. 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.

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. 

Three emphases were present in the conference, stress and the HPA axis, the autonomic nervous system, sleep and cytokines, and ‘central mechanisms’.

The HPA axis, stress and the immune system - The largest focus was on ‘stress’, 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’.

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.

The involvement of the HPA axis and the stress response in many different processes in the body suggests, however, that it could play a role in as multi-dimensional disease such as CFS. In particular it's role in immune regulation is intriguing given the suggestion of immune involvement in CFS. Indeed, some studies have found a disturbed neuro-immune interface in 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). That and his finding that the IL-10 production triggered by bacterial lipopolysaccharides is higher in CFS could reflect altered HPA axis activity.  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 mixed evidence of an altered neuroendoimmune interface in CFS.

Esther Sternberg’s engaging talk on ‘Health Consequences of a Dysregulated Stress Response’ illuminated how reduced HPA axis responsiveness could lead to an out of control inflammatory response. Rats (Lewis) genetically engineered to have a hyporesponsive HPA axis develop autoimmune inflammatory diseases when they are exposed to pathogens. This is an intriguing finding given the propensity of CFS to be ‘triggered’ by an infectious event. Sternberg reported that if the HPA axis ‘is blocked at any point and in any way’ formerly inflammatory resistant laboratory animals will ‘become highly susceptible to inflammation’. (CFS patients appear to display reduced CRH and cortisol levels and markers of inflammation.) Sternberg also points out that sympathetic nervous system activity appears to be reduced in Lewis rats possibly because these rats appear to missing a portion of the hypothalamus that stimulates the autonomic nervous system. This suggests that low CRH production could result in reduced ANS activation. Since the ANS plays a key role regulating immune function reduced CRH production in this part of the hypothalamus could result in immune dysregulation.

Sternberg believes subtle changes in genes regulating the neuroendocrine/immune response could predispose people to CFS. One of the genes differentially expressed in Lewis rats involves a thyroid transporter, transthyretin – an interesting finding given the fatigue seen in both CFS and thyroid dysfunction. Since thyroid tests in CFS are usually negative this produces a mechanism that could explain the paradox between the usually normal levels of thyroid hormones in CFS and the symptoms of ‘hypothyroidism’ often seen.  

Most of Firdaus Dhabhar’s talk on ‘Stress and the Augmentation of Immune Function’ focused on the effects of acute stress on cortisol production and the immune response, a questionable topic given the fact that it is chronic not acute stress that is believed to be operative in CFS. In response to a question Dhabhar suggested that IL-4/IL-10 could be upregulated in CFS and the intriguing notion that the acute stress response might have become lost over time in CFS. Recent studies have indicated increased IL-4 or IL-10 production in CFS. Since Il-10 production appears to be suppressed more than usual by the HPA axis in CFS patients, but appears more greatly increased by SNS (beta adrenergic) activation in CFS patients, it appears, at least at this point, that beta adrenergic functioning is more applicable to CFS than HPA axis functioning. The activities of the SNS, the other major stress responder in the body were, however, barely addressed in this conference. .

Juan Lopez’s talk (Stress and Antidepressant Modulation of the Limbic HPA Axis) largely dealt with a usually minor treatment modality (antidepressants) in CFS and thus was mostly not informative. Lopez did present the intriguing suggestion that brain dysregulation could occur through attempts to keep cortisol levels normal. He also suggested that glucocorticoid down regulation could result in reduced serotonin (5-HT) receptor activity. Some studies indicate CFS patients display reduced 5-HT R activity. He also posited that HPA axis dysregulation may need to be corrected before antidepressants work in CFS.

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 could contribute both to impaired sleep and to reduced wakefulness and fatigue found in CFS.  Cytokines have been a focus of research since substantial numbers of CFS patients first started reporting that flu-like symptoms accompanied the onset of their disease. The results of cytokine studies in CFS have been mixed but Nancy Klimas posits that poor laboratory techniques could account for some of the negative findings in CFS.

In James Kreuger’s talk on the ‘Mechanisms Underlying the Central Effects of Cytokines’, he said it was ‘likely that the fatigue and sleepiness associated with chronic fatigue, regardless of etiology, are associated with changes in …three molecules"; growth hormone releasing hormone (GHRH), interleukin-1 (IL-1) and tumor necrosis factor (TNF-a)). Il-1 and TNF-a are pro-inflammatory cytokines that have been shown to effect brain functioning. Krueger noted that IL-1 activation is very closely related to GHRH activation and that mice with reduced GHRH activity sleep less than normal when infected with influenza. The dose dependent effects of IL-1 and TNF-a indicate that that low levels of each induce sleep while high levels impair sleep. Despite Krueger’s assertion that these molecules are probably involved in the fatigue seen in CFS none of his talk involved fatigue.

Richardson’s talk on "Corticotrophin-releasing Hormone, Insomnia and Depression" suggested that hyperactivation of the SNS could lead to insomnia. There is evidence that insomniacs may not be unable to return their stress levels to normal after the stress is removed. Intriguingly given the high salt diet of many CFS patients Richardson noted that low salt diets result in SNS activation and reduced sleep quality. Could high salt intake in CFS be an attempt to dampen SNS activity? In contrast to CFS patients, however, primary insomniacs displayed high not low cortisol levels.

In Mark Opp’s talk on ‘Cytokine-Neurotransmitter Interactions and the Regulation of Arousal State’ he noted that every major neurotransmitter system and well as the IL-1 and TNF-a cytokines, and  the CRH  hormone are all involved in regulating sleep/awake behavior. The reduced CRH levels in Lewis rats results in increased sleep and reduced wakefulness. Increased CNS IL-1 production results in increased levels of non-REM sleep. Glucocorticoid activity at the hippocampus and hypothalamus regulates IL-1 and TNF-a synthesis in the brain. Experiments using laboratory animals indicated that reduced glucocorticoid expression (as may occur in CFS) resulted in dramatically increased IL-1 production in the hippocampus, brain stem and cortex.

Adler’s talk on the ‘HPA Axis and Autonomic Nervous System Function in Fibromyalgia’ began with a discussion of circadian rhythm. Neither CFS patients or FMS appear to overtly altered circadian rhythms. A recent study indicated, however, that melatonin therapy was helpful in CFS. Both CFS and FMS patients do appear to exhibit mildly reduced HPA axis activation. HIs talk on hypoglycemia was intriguing. Hypoglycemia turns on the HPA axis but hypoglycemic patients treated with cortisol induce a feedback mechanism that turns off CRH and ACTH. If during this period cortisol is withdrawn the hypoglycemic patients display many of the symptoms seen in CFS (fatigue, malaise, muscle aches, gastrointestinal complaints, dizziness upon standing, nausea, etc.). She, then, however, presented evidence indicating that such a process did not apply to FMS (!) but suggested that low CRH levels in FMS patients could result in increased ACTH responsivity. She explained that stress induced rises in cortisol could by inhibiting CRH inhibit ACTH and the hormonal and autonomic response to stress. This theory was interesting but didn’t appear to fit either CFS or FMS both of which have reduced or normal levels of cortisol.

In Linda Toth’s talk on the ‘Genetics of Sleep Regulation’ she noted that mice with a predominant Th2 response and reduced IFN production sleep less when infected with a pathogen than do mice with a predominantly Th1 (cytotoxic T-cell) response. Some researchers believe CFS patients display a predominantly Th2 dominated immune response. While Toth did not speculate why she noted that even after the Th2 mice cleared the virus they still slept less than before. CFS patients can fit on both sides of the sleep gradient; some sleep enormous amounts, others are insomniacs. She very aptly noted that reduced sleep is not fatigue and that it is very difficult to differentiate the two in laboratory animals.

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.

Margaret Heitkemper’s talk on ‘Sex and Gender Issues in Multisystemic Illnesses’ which focused entirely on Irritable Bowel Syndrome (IBS), a disorder of some interest to CFS patients, was interesting, but one wondered why a researcher associated with IBS spoke at a conference on CFS when so many CFS researchers did not.

While IBS patients primarily have problems with pain and CFS patients have more problems with fatigue, both often display unrefreshing sleep and increased incidence among women. Similar explanations have been advanced for both; that the patients with each are hypersensitive to stimuli, that their problems are infection related and (in IBS) they display poor bowel motility. A recent study found CFS patients displayed prolonged gastric emptying.

Some studies suggest that early childhood stress may be a risk factor for both IBS and CFS, and that it is associated with increased anxiety and depression. Current models of IBS (and CFS) suggest problems with the neuro-immune (gut) interface. Increased IBS symptoms during a part of the menstrual phase characterized by low estrogen or progesterone levels suggests a hormonal component. Studies have shown that low estrogen decreased gut motility, a phenomena that may involve reduced nitric oxide production. A recent study found reduced mRNA levels of the estrogen receptor in CFS. The authors suggested estradiol supplementaton.

Stress can be a trigger for both IBS and CFS. The greater sympathetic nervous system response that men display to stress has been suggested to shield them from conditions such as IBS and CFS. Autonomic nervous system examinations found higher levels of morning catecholamines (SNS activation) and, as in FMS and CFS, reduced heart rate variability, and reduced parasympathetic nervous system activity (vagal tone) during sleep.  A recent study also found reduced sleep HRV in CFS patients relative to controls. Both pain and mood disorder were, interestingly enough, was negatively correlated with vagal tone.

Heitkemper noted that the vast majority of serotonin found in the body is in the gut. The close connection particularly serotonin rich cells have with the mucosal surfaces and nerve endings in the gut, suggests serotonin dysregulation could play a role in the pain experienced by IBS patients.

Lastly Heitkemper reported that a CBT trial in IBS did reduce symptoms and increased quality of life but failed to alter the increased catecholamine levels or autonomic nervous system imbalance. Several studies have indicated increased serotonergic activity in their brains of CFS patients. This subject was, unfortunately, barely discussed in this conference.

Denise Park’s talk on ‘The Cognitive Neuroscience of Fibromyalgia’ suggested that FMS patients displayed ‘cognitive aging', i.e. cognitive impairments in memory associated tasks similar to those found in people 20 to 30 years older. A fMRI study also found that FMS patients displayed the same kind of increased brain matter activation during a task as do older people. Two recent fMRI studies have found increased brain activation in CFS as well. Park’s talk elucidated the cognitive problems present in FMS but did little to attempt to explain them, an unfortunate omission given the goal of the conference. While her talk was informative one wonders, once again, why a FMS rather than a CFS researcher gave this talk.

Jon-Bar Zubieta’s talk (Brain Stress-Response Circuitry in the Regulation of Physical and Affective States) was one of the more engaging. In it he weaved together genes, the gender differences in CFS and the endocrine, immune and nervous systems to produce a model that could explain some of the symptoms of CFS. This kind of comprehensive presentation was, unfortunately, lacking at this conference. 

This talk mostly concerned the performance of opioid receptors that regulate the peptide neurotransmitters released in response to inflammation and pain. Zubieta noted that pain prompts the production of ACTH and cortisol which in turn activates opioid neurotransmission in several areas of the brain (anterior cingulate, thalamus and basal ganglia). Several researchers think these areas may be impaired in CFS. It turns out that opioid neurotransmission does indeed serve as an ‘opiate’ - it reduces pain.

Zubieta has found that a) women are less efficient at activating this pain reducing process than men and that b) both sexes demonstrate great individual variability in their ability to do so. Tests of muations in an enzyme (COMT) that plays a key role in metabolizing the neurotransmitters released during opioid neurotransmission (dopamine, norepinephrine) indicated that people carrying one polymorphism were less efficient at inducing the pain suppressing process. Indeed, reduced dopamine and opioid receptor binding have been found in chronic inflammatory and pain conditions.

Of course CFS is not FMS or regional pain syndrome i.e. it is not a ‘pain disease’ but Zubieta points out that these diseases share other symptoms (poor attention, concentration, difficulties in tolerating stress, mood changes, etc.) that could be due to dysregulated opioid neurotransmission. With regards to CFS he suggests a persistent infectious state in common with a genetic predisposition to the COMT polymorphism, which is found in 20% of the population, could result in a vulnerability to CFS.

Zubieta’s conclusions were challenged by one panel member but it was notable that in a conference on CFS he was one of only two researchers able to produce a model that actually specifically focused on CFS. 

CFS Researchers

Only three of the presenters (Klimas, Zubieta, White) had published broadly on CFS and 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 a very important topic for those doing immune research in CFS, but did nothing to actually illuminate the neuroimmune interface.  One wonders why she was asked to speak at this conference. 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 it was alarming that the only prominent CFS researcher present with a background in neuroimmunology is also one of the foremost advocates of the idea of CFS as a disease of poor coping skills. 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 a further exploration of this area. This could hardly have surprised the organizers of the conference who apparently went to some expense to ensure he spoke; he was the only presenter located outside the U.S.

A Conference on Chronic Fatigue Syndrome (?)

There was actually little discussion of CFS. Researchers either did not (Adler, Opp) or hardly mentioned (Dhabhar, Kruger, Lopez, Sternberg) CFS in their talks. Remarkably, even David Goldstein,  the Chair of a session on the autonomic nervous system - another area of great interest in CFS - was unable to relate any of his findings to CFS or to suggest fruitful avenues of research. His remarks on CFS were limited to one paragraph.

Indeed 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 on 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 does take place that the presenters will be knowledgeable on CFS and the focus  of their talks will be on CFS.

Alternatives – While some of the talks were very informative there is an evolving field of research involving neuro-immune mechanisms and fatigue that was mostly ignored

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 common. Several areas of potential interest were apparently ignored while the organizers focused on the HPA axis and sleep. While the talks focused on the effects HPA axis alterations can have on the immune system were informative, 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.  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 focus of this conference what can we expect from the Neuroimmune RFA? Probably a focus on HPA axis/immune interactions, sleep and ‘stress’. A series of grants focused solely on those topics would, however, be disappointing. One must also worry, given the significant proportion of talks on illnesses other than CFS, about how many 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 of a subset of CFS patients. 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, is consistently  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. The current research, then, continues to suggest the neuro-immune interface is a vital one  in CFS.  Hopefully the RFA grants awarded will reflect that promise.

 Neuro-Immune RFA Intro / The RFA Grant / Reviewing the Reviewers / Conclusion: Assessing the Grants

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Cleare AJ, Messa C, Rabiner EA, Grasby PM. 2005. Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biol Psychiatry.;57:239-46.

Freeman R, Komaroff AL. 1997. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med. 102(4):357-64.

Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH, Ehlert U. 2002. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002 64(2):311-8.

The GK, Prins J, Bleijenberg G, van der Meer JW.. 2003. The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients--a pilot study. Neth J Med.;61(9):285-9.

Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. 2000. J Clin Endocrinol Metab. 85(2):692-6.

Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H. 2003. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochem Biophys Res Commun.311(2):264-6.

Stewart JM. 2000 Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 48 :218-26.

Streeten DH, Thomas D, Bell DS. 2000. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 320(1):1-8.

Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L. 2001. LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. J Neuroimmunol. 119(2):343-9.

Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. 2001. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors.
J Investig Med. 49(2):195-204.

Visser J, Blauw B, Hinloopen B, Brommer E, de Kloet ER, Kluft C, Nagelkerken L. 1998.CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone.
J Infect Dis.177(2):451-4.

Yamamoto S, Ouchi Y, Onoe H, Yoshikawa E, Tsukada H, Takahashi H, Iwase M, Yamaguti K, Kuratsune H, Watanabe Y.. 2004. Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport. (17):2571-4.