Altered Lymphocytes in Chronic Fatigue Syndrome
Isabel Barao, Ph.D., Simmaron Research
Results: We found unusual
increases in a 'hybrid' population of lymphocytes in CFS patients. This
population has features of both T cells and NK cells and is normally 1-5% of
all lymphocytes but can be as high as 30% in the CFS patients. Interpretation:
The results are consistent with altered immunity in CFS patients, particularly
altered immune responses to chronic viral infections. Further characterization,
including repeated tests of the same patients, is needed to determine if this
unusual population is persistent and to determine if it can mediate
cytotoxicity towards virally infected cells.
Interestingly a 2008 study Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: An exploratory analysis (Jim Fuite et. al) published in Science Direct, quite extensively looked at the immune demography and identified critical failures and body’s adaptation patterns to the health condition. The Abstract & Discussion copied below. So, what are we talking suddenly about ‘altered immune system’ now. Rather, research should have progressed fast in the last 2 decades. What happened to the above 2008 study...no progress???
What worries me is that, there is no
scientific or medical honesty when it comes to research and developing a cure
for ME CFS. It took decades to accept that ME is a health condition and it has a
biological origin. What is more tragic is neither adequate funds were invested,
and even the intended funds were diverted by CDC and more over, completely
failed on taking research forward in a scientific manner.
Abstract
This work
investigates the significance of changes in association patterns linking
indicators of neuroendocrine and immune activity in patients with chronic
fatigue syndrome (CFS). Gene sets preferentially expressed in specific immune
cell isolates were integrated with neuroendocrine data from a large
population-based study. Co-expression patterns linking immune cell activity
with hypothalamic–pituitary–adrenal (HPA), thyroidal (HPT) and gonadal (HPG)
axis status were computed using mutual information criteria. Networks in
control and CFS subjects were compared globally in terms of a weighted graph
edit distance. Local re-modeling of node connectivity was quantified by node
degree and eigenvector centrality measures. Results indicate statistically
significant differences between CFS and control networks determined mainly by
re-modeling around pituitary and thyroid nodes as well as an emergent immune
sub-network. Findings align with known mechanisms of chronic inflammation and
support possible immune-mediated loss of thyroid function in CFS exacerbated by
blunted HPA axis responsiveness.
Discussion
This study provided a comprehensive overview of changes in mutual
information linking 37 indicators of neuroendocrine and immune function in CFS.
Instead of constructing a single graph from differentially expressed nodes, we
identified weighted graphs for NF and CFS separately enabling us to study
characteristic changes in graph structure. Though the overall abundance of
connections was conserved in both networks, they differed significantly in the
distribution of highly connected nodes. Indeed the subtle re-modeling observed
in CFS might well be a hallmark of many chronic disorders where homeostasis is
maintained albeit with significantly altered function. CFS yielded an increase
in network centrality making information flow through this network more highly
dependent on a smaller number of hub nodes. In statistical physics a network
increases in centrality [20] as it loses
energy, a process thought to mitigate the impact of unstable feedback in living
systems [21]. However in these
networks the loss of a hub node is also more likely to cause catastrophic
failure. Interestingly, as the neuroendocrine portion of the network re-modeled
to a lower energy configuration in CFS, the immune portion morphed into a
higher energy configuration.
Driving this shift in topology were significant changes in
coordinated activity between the pituitary, the thyroid, the ovaries and the
immune system. This was especially noticeable in terms of eigenvector
centrality which doubled in CFS for nodes such as ACTH, TSH and free T4.
ACTH-driven cortisol synthesis alters the cytokine profile in T cells via its
effects on monocytes and other antigen-presenting cells leading to the
termination of unwanted autoimmune inflammatory reactions [22]. Hypocortisolism
has been observed in CFS with possible ties to ACTH unresponsiveness [23] and [24] and increased sensitivity to glucocorticoid [25] feedback.
Interestingly the current study linked the disassociation of ACTH from immune
activity in CFS to the emergence of a monocyte-neutrophil-B cell inflammatory
network rooted in known immune biochemistry [26]. Despite this
ongoing inflammatory response, ACTH was only marginally more distant from
cortisol in CFS further supporting the notion of a loss in HPA axis control.
Inflammatory cytokines are known to inhibit thyroid function [27] and thyroid
autoimmunity has been linked to diabetes and ovarian failure [28]. Recall we found a
close association of free T4 with both insulin and progesterone in CFS (Fig. 4b). In fact one
of the most striking results in this study involved the re-organization of
network structure around the free T4 node. This node was directly linked to
monocyte, NK, T and B cell nodes in CFS. Association with NPY, a monocyte
mediator [29] and C reactive
protein (CRP), an acute phase inflammatory protein, implicate a possible immune
response directed at the thyroid. Estradiol priming is essential to thyroid
function [30] and [31] in addition to promoting growth hormone (GH)
synthesis by the pituitary and subsequently insulin-like growth factor (IGF1).
IGF1 is a potent activator of cell proliferation and the resolution of
inflammation. Free T4 disassociates from estradiol and testosterone in CFS
acquiring instead a direct link to sex hormone-binding globulin (SHBG), a
glycoprotein that suppresses bioavailability of both of the former. Reduced
bioavailability of estradiol can hamper GH and IGF1 synthesis leading to
deficient tissue repair consistent our observations of unresolved inflammation.
Though impaired GH response has been observed in CFS [32] the current work
provides novel insight into a suspected but so far unsubstantiated link to IGF1
insufficiency and inflammation.
These observations illustrate the interplay between the HPT and
HPA axes. Approximately half the androstenedione, a precursor of estradiol, is
produced by the adrenal glands in pre-menopausal women where it is governed by
ACTH [33]. The loss of a
direct link between ACTH and estradiol nodes was another indication of adrenal
disturbance in CFS. As discussed previously, loss of adrenal function would
have dual implications, not only releasing the inflammatory response from the
control of cortisol but also impairing the cellular repair response by robbing
the pituitary of estradiol stimulation in GH and IGF1 synthesis. This scenario
is only exacerbated in post-menopausal women by virtue of their dependency on
adrenal androstenedione and subsequent estradiol synthesis. Interestingly,
there are increased rates of thyroid disease [34] and CFS [35] in women.
By conducting a comprehensive examination of the changes in
neuroendocrine and immune signaling in CFS, this study provided novel evidence
of a pattern of failure occurring across multiple physiological systems. Some
of the changes may be linked to CFS etiology while others may reflect the
body's adaptation to this chronically fatigued state. Studies of incident CFS
will be needed to determine if neuroendocrine and immune network re-modeling in
arises as a result of CFS or as a driver thereof.
