By Rich Van Konynenburg, Ph.D.
Dr. Esther Sternberg gave a talk at the NIH CFS workshop on June 12, 2003 in Bethesda, MD on the subject of "Health Consequences of a Dysregulated Stress Response." Dr. Sternberg is the Director of the Integrative Neural Immune Program and Chief of the Section on Neuroendocrine Immunology & Behavior of the National Institute for Mental Health of the NIH. She is an expert on the interaction between the brain, the endocrine system and the immune system.
Before discussing her talk, I want to give some background that I hope will set the scene. First, I think there is quite a bit of evidence in the literature and in the personal experience of many individual PWCs, that prior to the onset of Chronic Fatigue Syndrome (CFS) (especially for those with rapid or sudden onset) there is often found a history of a combination of various kinds of stress that is experienced as long- term and severe. But since not everyone who experiences such stress develops CFS, it seems likely that the genetic makeup of PWCs is also an important factor determining whether they will develop CFS. There seems to be a growing consensus developing about disease in general these days that it results from an interaction between a person's genetic makeup and some external influence, be it a toxin, a pathogen, emotional stress, or some other factor, including lifestyle factors such as nutrition. So the important points here are that stress appears to be a significant factor in the onset of many cases of CFS, and genetic makeup is probably also important.
The next point I want to make is that it is known that the main system by which the body responds to stress is the hypothalamus-pituitary-adrenal (HPA) axis. Various inputs to the hypothalamus from different parts of the brain convey information to it about stresses of various types that are being experienced by the body. In response to these signals the hypothalamus secretes CRH (corticotropin releasing hormone). This hormone causes the pituitary gland to secrete ACTH (adrenocorticotropin hormone), which in turn causes the cortices of the adrenal glands to secrete glucocorticoids, the principal one being cortisol (also called hydrocortisone). In a normal, healthy person, there is a negative feedback operating that communicates between the adrenals, the pituitary and the hypothalamus and keeps the cortisol level properly controlled.
In addition to the action of the HPA axis, stress also causes the sympathetic nervous system to be activated. The sympathetic nervous system signals the medullas of the adrenal glands to secrete adrenalin and noradrenalin.
The next important point is that it is known that the HPA axis and the sympathetic nervous system affect the operation of the immune system. Since we know that the immune system is dysregulated in CFS, it is thus not a big stretch of the imagination to suspect that at least some of this immune dysregulation might be caused by action of the HPA axis and the sympathetic nervous system in response to stress. I think this is the reason Dr. Sternberg was invited to speak on neuroendocrine aspects of the stress response and how they influence the immune system.
One of the main points Dr. Sternberg made is that if the HPA axis is upregulated, so that the glucocorticoid secretion is elevated, the effect on the immune system is to suppress it. This includes suppressing inflammation, but also suppressing the Th1 immune response, which defends against viral and intracellular bacterial infections in particular, and shifting the immune response to Th2. It also causes prolonged wound healing and a decreased production of antibodies when a vaccine is given. On the other hand, if the HPA axis is blunted or downregulated, the effect on the immune system is to promote inflammation. This includes autoimmune inflammatory diseases.
In her handout, Dr. Sternberg noted that the noradrenalin and adrenalin produced in response to the sympathetic nervous system also induce a Th1 to Th2 immune response shift.
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Dr. Sternberg discussed the different immune responses of Lewis and Fischer rats, which are inbred types of rats that have somewhat opposite HPA axis behaviors because of genetic mutations. They serve as models for people who have either up- or down-regulated HPA axes. By manipulating these rats surgically or pharmacologically, researchers have been able to change their response to inflammatory stimuli. Dr. Sternberg emphasized that the rats that were genetically prone to inflammation did not actually develop it unless they were exposed to appropriate stimuli, such as pieces of bacteria.
She also discussed the observed higher prevalences of inflammatory autoimmune diseases in women. The prevalences are two to tenfold higher in women than in men. Higher prevalences are also found in female rats than in male rats. She noted that estrogen plays a major role in modulating the immune system, and suggested that this is particularly important during pregnancy, when the balance between the glucocorticoid and estrogen regulation of the mother's immune system probably is what prevents rejection of the fetus. (It may be that this feature of the control of the female immune system is involved in the observed higher prevalence of CFS in women than in men.)
Dr. Sternberg suggested that there may be genetic factors, developmental factors and environmental factors involved in CFS, based on experience with rat models and with inflammatory diseases in humans.
Here's my view of the significance of what Dr. Sternberg discussed for CFS:
It looks to me as though CFS onset occurs when a person with a certain genetic makeup is subjected to a long-term combination of various types of stress. The result is that the HPA axis and the sympathetic nervous system respond to the stress by becoming upregulated for a long time, raising the secretion of glucocorticoids, adrenalin and noradrenalin, and that these cause a strong Th1-to-Th2 immune response shift.
(Something Dr. Sternberg didn't discuss, but which I think also comes into the picture here, is that there is a depletion of glutathione, partly as a result of the oxidation of some of the adrenalin and noradrenalin to form o-quinones, which are detoxed in phase-2 detox using glutathione. Glutathione depletion is also known to promote the Th1-to-Th2 shift.)
As a result of the shift to Th2, the body does not have an effective defense against viral or intracellular bacterial infections. Several types of viruses (such as Epstein-Barr) are already present in the cells of the body of most people in the latent state. They become activated and produce infections. The immune system attempts to respond, but is not able to do so effectively because of its suppression by the HPA axis and the sympathetic nervous system. In its attempt, it further drains the body's supply of cysteine to make glutathione, robbing the skeletal muscles of their supply, as Bounous and Molson hypothesized. The muscles thus go low in glutathione, and the oxidizing free radicals there (including peroxynitrite) rise in concentration, blocking their metabolism and producing the fatigue.
Later on in the pathogenesis, the HPA axis becomes blunted or downregulated. I think this occurs because of a direct attack on the hypothalamus. I don't know whether this is due to toxins, pathogens or oxidizing free radicals, or some combination, but elevations in all of these are known to result from glutathione depletion, and the hypothalamus is not protected by the blood-brain barrier. Even though the HPA axis becomes downregulated, there is still not an effective Th1 response to attack the viral infections, because of the glutathione depletion at this point. However, the downregulated HPA axis now opens the PWC up to inflammation, and this explains things such as the high prevalence of Hashimoto's thyroiditis and elevated antinuclear antibody. The PWC thus ends up with the worst of both worlds, with no effective protection from either the viruses and the intracellular bacteria or from inflammation.
I think this makes a very believable front end to the story of how CFS gets going in at least the sudden or rapid onset cohort. It remains to identify the genetic polymorphisms that predispose some people to CFS when subjected to the appropriate long-term stress combination. I suspect that the relevant polymorphisms will be found in some part or parts of the operation of the HPA axis or the immune system or both. It makes sense to me that they would have to be located in systems involved in the early part of the pathogenesis of CFS in order to be accessed, and thus to be relevant to increasing the probability of going on to onset of CFS.