A report in this morning’s Science Daily News started a cascade of its own as several pieces of the puzzle clicked into place. With the charming title of
It goes on to state “”…. researchers from the University of Connecticut Health Center have found that the same part of our nervous system that is responsible for the fight-or-flight response (called the sympathetic nervous system) also controls regulatory T cells, which are used by the body to end an immune response once a foreign invader has been removed or destroyed.”
So, here is a link between the endocrine system’s fight or flight response and the immune system’s method of ending an immune response (which fails in the case of PD) with the nervous system’s sympathetic division being responsible for both. Is it possible that events impacting the endocrine stress system could act upon the sympathetic nervous system in such a way as to impinge upon its ability to end an immune response that is no longer needed?
Looking a little further – it is often reported that people experienced traumatic events in the couple of years prior to their first PD symptoms. How does trauma affect regulatory T cell populations and thereby the control of the immune system’s ability to halt an inflammatory response? That question led to this:
Brain Behav Immun. 2009 Nov;23(8):1117-24. Epub 2009 Jul 18.
Substantial reduction of naïve and regulatory T cells following traumatic stress.
Division of Immunology, University of Konstanz, Konstanz, Germany.
Posttraumatic stress disorder (PTSD) is associated with an enhanced susceptibility to various somatic diseases. However, the exact mechanisms linking traumatic stress to subsequent physical health problems have remained unclear. This study investigated peripheral T lymphocyte differentiation subsets in 19 individuals with war and torture related PTSD compared to 27 non-PTSD controls (n=14 trauma-exposed controls; n=13 non-exposed controls). Peripheral T cell subpopulations were classified by their characteristic expression of the lineage markers CD45RA and CCR7 into: naïve (CD45RA(+) CCR7(+)), central memory (T(CM): CD45RA(-) CCR7(+)) and effector memory (T(EM): CD45RA(-) CCR7(-) and T(EMRA): CD45RA(-) CCR7(-)) cells. Furthermore, we analyzed regulatory T cells (CD4(+)CD25(+)FoxP3(+)) and ex vivo proliferation responses of peripheral blood mononuclear cells after stimulation with anti-CD3 monoclonal antibody. Results show that the proportion of naïve CD8(+) T lymphocytes was reduced by 32% (p=0.01), whereas the proportions of CD3(+) central (p=0.02) and effector (p=0.01) memory T lymphocytes were significantly enhanced (+22% and +34%, respectively) in PTSD patients compared to non-PTSD individuals. To a smaller extent, this effect was also observed in trauma-exposed non-PTSD individuals, indicating a cumulative effect of traumatic stress on T cell distribution. Moreover, PTSD patients displayed a 48% reduction in the proportion of regulatory T cells (p<0.001). Functionally, these alterations were accompanied by a significantly enhanced (+34%) ex vivo proliferation of anti-CD3 stimulated T cells (p=0.05). The profoundly altered composition of the peripheral T cell compartment might cause a state of compromised immune responsiveness, which may explain why PTSD patients show an increased susceptibility to infections, and inflammatory and autoimmune diseases.
PMID: 19619638 [PubMed – indexed for MEDLINE]
So here we have T cells, essential for communication of stand down orders within the immune system, suffering a 50% reduction in population due to trauma. If the unfortunate individual was one with an unusual sensitivity to bacterial toxin LPS due to early life events and was barely able to control the microglia anyway, what does a loss of half his communication ability do?
And what does this say about the rather large sub-group of PWP who report unusually traumatic childhoods? If they had also experienced LPS hypersensitivity, would they not have a similar problem?
Stress (trauma) reduces the ability of the sympathetic nervous system to regulate immune response which, in turn, allows the runaway microglial activation that ultimately damages the substantia nigra and reduces motor symptoms.
PD is a complex creature and difficult to understand. One way to overcome this problem is by using analogies to make it comprehensible. If a picture is worth a thousand words, then a good analogy is just as valuable.
One major feature of YOPD is the struggle to maintain homeostasis, or balance, in the mind and body. Like Goldilocks, one bowl of soup is too hot, one is too cold, but that one that is just right is what we are looking for. Constantly. One does not achieve balance and then take the day off. The pursuit of health, of homeostasis, in a sense IS living.
A healthy person is like a spinning top. Perhaps you remember playing with these as a child. One would wind a string about the top and, with practice, deftly flick the wrist while holding the end of the string. If all went well. the unwinding string imparted a brisk spin to the toy which then settled into a magical stability.
Like the top, we are born with a certain amount of “spin”. If you nudge a spinning top, it resists falling over and does so in direct relationship to the amount of spin. It will wobble slightly and then right itself. However, repeated nudges or single ones of larger magnitude produce greater wobble and more energy is drained from the system. Eventually, time takes its toll and the lovely order of spin dissolves into an undignified collapse.
That is the way our own bodies behave and this system for maintaining stability grows increasingly “dysregulated” in YOPD.
Fetal encounters with the bacterial waste products from maternal infections are common. However, in order for them to cause serious problems, these encounters must occur during the short time that critical structures are forming. The results of fetal exposure to the bacterial endotoxin lipopolysaccharide (LPS) can have several pro-parkinson’s effects.
Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism to the emergence of neurochemical imbalances in adulthood, which may be critically involved in the precipitation of adult behavioural and pharmacological abnormalities after prenatal immune challenge. (Meyer 2009)
Thus, exposure to the bacteriotoxin, lipopolysaccharide (LPS) during a critical developmental window in rats, leads to the birth of animals with fewer than normal dopamine (DA) neurons. This DA neuron loss is apparently permanent as it is still present in 16 months old animals (the longest period studied to date). Moreover, the loss of DA neurons seen in these animals increases with age thereby mimicking the progressive pattern of cell loss seen in human PD. (Carvey 2003)
One is a reduced density of dopaminergic neurons in the substantia nigra and another is hypersensitivity to further exposure – the system is “primed”. Future exposure to LPS, particularly after the changes of puberty, will trigger a greater reaction whose magnitude will vary with individual sensitivity.
Sensitivity to LPS is genetically determined, varying considerably among different species. The sensitivity of normal animals (mice) to endotoxin may be enhanced considerably under different experimental conditions that include treatment with live (infection) or killed Gram-negative and -positive bacteria. (Fruedenberg 1993)
We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson’s disease. (Carvey 2004)
Thus, this disrupted immune system can lead to chronic inflammation and microglial activation with elevated levels of cytokines and related pro-inflammatory chemicals leading to “cell death.
The twin roots (immune and endocrine) of Parkinson’s Disease reaching back to the earliest moments of existence represent the extreme of a spectrum of causal scenarios and produce the earliest onset of symptoms. The two arise together and interact to produce the disorder by means of a self-perpetuating immune-endocrine reaction.