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Summary: Nancy Klimas, M.D.’s Talk at the NIH Chronic Fatigue Syndrome Workshop

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By Rich Van Konynenburg, Ph.D.

Nancy Klimas, M.D., is a Professor of Medicine, Psychology, Microbiology and Immunology at the University of Miami School of Medicine. She is the Principal Investigator of one of the three NIH sponsored CFS Research Centers. She has conducted research on the immunology of CFS since the late 1980s. Her talk at the NIH CFS workshop on June 12, 2003, focused on the immune dysfunction observed in CFS. She reported on a critical review of the published papers in this field, presented what appeared to her to be the consensus of this work, discussed the problems with the existing data and the difficulties in measuring immunological parameters, and suggested guidelines for future efforts in this field.

In summarizing the published work, the main conclusions she presented were that there are a lot of data indicating that there is chronic immune activation in CFS, that there is a fair amount of data demonstrating that there is a shift to a Th2 type of immune response, there is considerable data showing that there are changes in cytokine expression, and there are a lot of data showing lowered natural killer cell activity (low NK cell cytotoxicity). In addition, she noted that there is evidence for elevated numbers of immune complexes, elevated levels of antinuclear antibodies (ANA), higher prevalence of allergies, and an activated RNase-L pathway.

(Briefly, here's what these things mean: Chronic immune activation means that the T lymphocytes, a type of white blood cell that coordinates the activities of the immune system, show evidence that they have been alerted to the presence of a threat, and they continue to remain in this alerted state, whereas normally they would return to the inactivated state after the threat was defeated.

The shift to a Th2 immune response means that instead of maintaining a balance between a cell-mediated or Th1 type of immune response and a humoral or Th2 type of response, the immune system has shifted to a Th2 response and stays "locked into" this type of response. These two modes are both needed in order to have protection against both normal bacteria, which stay outside the human cells, and viruses and intracellular bacteria, which enter human cells. Th1 operates by killing infected human cells.

Th2 operates by making antibodies, which attach to normal bacteria and other pathogens that are outside human cells, so that they can be marked for killing by cells specialized for this job. Both are needed, but in CFS, the Th1 response is missing. Cytokines are chemical messengers that are made by white blood cells of various types to signal each other, in order to coordinate the overall immune response. They are also used to communicate from the immune system to parts of the brain. For example, some of them carry a signal to the hypothalamus to produce a fever. Different patterns of cytokine concentrations are found in the blood during Th1 and Th2 immune responses, and this is one way to identify the type of response that is dominant.

The natural killer cells are a type of lymphocyte (a white blood cell) that is normally able to kill infected cells without having to be cloned specifically for a particular type of infection hence, they are "natural" killers that are versatile enough to kill any infected human cells that aren't signaling that they are uninfected. Immune complexes are combinations of antigens and antibodies to them that are joined together in a "clump."

An antigen is usually a protein that is part of a virus or a bacteria, or something else that's "foreign." An antibody (also called an immunoglobulin) is a protein that is made to recognize a specific antigen and bind to it. Antinuclear antibodies are antibodies against the nuclei of human cells. Allergies are cases in which the immune system unfortunately responds against something that is not actually a threat.

The RNase-L pathway is a pathway in all cells that can be activated by viral infections or toxins and that results in destruction of messenger RNA, both that produced by viruses and that produced by the human cells themselves. Activation of this pathway is sort of a desperate move on the part of the cell to prevent the proliferation of viruses, while at the same time interfering with the ability of the cell to make its own proteins. It is analogous to an army firing artillery at its own soldiers' positions (hopefully they are in foxholes) in order to kill an enemy force that has overrun their positions.)

Nancy also noted that there is a correlation between immune parameters and symptoms. In particular, when low NK cell activity and elevated T-cell activation are combined together, they are found to correlate well with increased symptom severity. Patients with high cognitive difficulty are found to have high neopterin levels (Neopterin is produced by activated macrophages. A macrophage ("big swallower") is a type of cell that is able to engulf and digest another cell.)

Nancy also briefly mentioned the experiment in which her group removed lymphocytes from lymph nodes of PWCs, placed them in a culture designed to shift them to a Th1 type of immune response, and reinjected them into patients, successfully shifting the immune response temporarily away from Th2 in seven patients. Six of them exhibited significant improvement in cognitive function and fatigue for a while.

She also mentioned her group's work on PWCs who underwent the stress of Hurricane Andrew. This turned out to produce chronic stress for many people, because of severe damage to their houses (she mentioned roofs being blown off). They found that the PWCs who had lower cognitive difficulty also tended to have better immune function. Those with lower NK cell function also tended to have more severe fatigue and worse cognitive function.

Nancy also noted that her group has done some work to try to develop an understanding of the mechanism of the immune dysfunction. In particular, they have found that the NK cells in PWCs are low in perforin, which is the substance they normally use to punch holes in infected cells in order to inject granzymes to kill them.

Among the problems she mentioned with the existing data were that the populations studied were heterogeneous, were not well described, and were frequently too small for statistical significance to be achieved; the studies were performed over a period of about 15 years during which time the case definition for CFS changed; methodology was not standardized so that it is difficult to make comparisons between studies; the immune parameters change over the course of time because of remission relapse cycles, the monthly hormonal cycle in women, and the circadian rhythm, none of which were accounted for; and sufficient attention was not paid to the fact that immunological samples "do not travel well" and that the laboratories doing the analysis of samples must "know what they are doing."

For the future, she recommended longitudinal studies rather than cross sectional studies as were done in the past, and efforts to avoid these other problems noted in the past studies.

Here's my view of the significance of the things Nancy discussed:

First, it is clear that immune dysfunction is present in at least a substantial subset of PWCs. While the cause of this dysfunction has not been clearly identified in a scientific sense, it seems very likely to me that it arises because of the body's response to long-term stressors, which is probably influenced by genetic variations in different people.

Long-term stress is known to act on the immune system via the HPA axis and the sympathetic nervous system. I think this response involves an initial long-term increase in levels of glucocorticoids and catecholamines (adrenalin and noradrenalin), which is the normal response to stress. This is known to suppress the immune system, and particularly the Th1 immune response, which is essential for defending against viral, intracellular bacterial and fungal infections.

For reasons that are not yet understood, but which may involve genetic makeup, in some people this suppression is severe enough that the immune system becomes unable to mount a successful defense against endogenous viruses, intracellular bacteria, and fungi, such as yeasts. I suspect that this suppression involved depletion of glutathione (and cysteine), as a result of the detoxification of o-quinones resulting from the oxidation of the large amounts of catecholamines from the long-term stress response, as well as from other factors. Glutathione depletion has been observed and reported in CFS, and it is known to be another factor that can cause a shift away from Th1 and toward Th2.

Under this model, the observed immune system activation is explained as a response to the ongoing infections, which the immune system is unable to defeat. The shift to Th2 is explained initially by the long-term glucocorticoid elevation, and later by the glutathione depletion. The changes in cytokine expression reflect the shift to Th2 and the continued futile efforts of the immune system to organize itself to attack the infections.

The low NK cell cytotoxicity results from deficient perforin production, which in turn is caused by a shortage of cysteine, which occurs because of glutathione depletion. Perforin production requires large amounts of cysteine. Basically [to use a military analogy], the soldiers have no bullets, but their officers continue to shout orders to them to kill the enemy.

Under this model the elevated numbers of immune complexes would result from elevated production of antibodies from the Th2 shift, and elevated levels of antigens from the infections that are allowed to proliferate. The increased prevalence of allergies would also result from the Th2 shift, and probably the elevated ANA would as well. The activated RNase-L pathway occurs because of the failure of the Th1 immune response to appear and to defeat the intracellular infections. As Dr. Cheney has said, “the cavalry never arrives.”

The correlation between the parameters describing the immune dysfunction and the severity of symptoms suggests that they have a common cause. I suggest that this common cause is the depletion of glutathione (and cysteine). I suggest that PWCs operate just at the ragged edge of not having enough glutathione for their systems to function. If anything occurs to further lower their glutathione supply, they suffer in several ways simultaneously, because several systems are at this "ragged edge." A large demand for glutathione will push them over the edge into a crash, and it will take some time to rebuild their supply.

I suggest that the reason Nancy and her group were able to switch immune cells to Th1 in culture is that they used a culture medium that contained sufficient cysteine, which the cells did not have when they were in the body. When they were placed back into the body, they were able to avoid the shift back to Th2 for a while, but eventually the lack of sufficient cysteine shifted them back.

I ask the readers to please be aware that my interpretations of the immunological studies are unproven hypotheses and are subject to change as more is learned. Nevertheless, I think they have some evidential basis, and if nothing else, they are at least an attempt to tie these scattered observations together into a coherent picture that has some degree of fit with the rest of the disease process. I firmly believe that it is important in research always to have a hypothesis to shoot at in order to make progress in understanding.

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