Proteins in Bone Health, Development and Disease in Environmental Illness

Proteins in Bone Health, Development and Disease in Environmental Illness

Making A Case for Tregs and LPS in Multiple Chemical Sensitivity~!

If there is injury and disruption of activities of olfactory neurons that has a connection to memory- can alteration of these proteins be a factor in MCS because of alteration of signals that exist between them?

Different studies have shown some interesting things about the sense of olfaction. It would be interesting to understand better how long-term toxic exposures alter the general patterns of operation of receptors in neurons and what circumstances make one more vulnerable. Zhang expressed that gap junctons modulate activity and sensitivity of olfactory neurons that have been shown to have receptors for one odorant whereas, cortical neurons get imputs from a number of different ones. (Buck) Kay writes that when the nose is first exposed to odor the molecules are absorbed into the olfactory receptor cells that line the mucous membranes at the back of the nostrils.  There are some 350 varieties of these receptor cells, each specialized to detect certain odor molecules which convert this information into nerve impulses and then transmit them to the brain’s two olfactory bulbs (one for each nostril), which sit just behind the nose. The olfactory bulbs then translates the impulses into information the brain can understand and are sent on to the olfactory cortex where the "odor information" is processed.

Several recent studies show disruptions in the sense of smell are indicative of the early signs of diseases including Alzheimer's disease, autism, Parkinson's disease and schizophrenia. Dr. Wilson, an expert in the neurobiology of olfaction explains that olfaction is a unique "sense" because it has direct links to the amygdala that is important for regulating emotion and physiology and to the prefrontal cortex that is involved with cognition and planning.  He also points out that this connection is also the short path that links olfaction with memory. (Kay) As noted, olfactory disfunction is a "early-warning" sign of schizophrenia and Turetsky's data indicates structural and functional abnormalities run from the cortex to the olfactory system. "These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression." This is also in line with some of the most current hypotheses of neuroinflammation and epigenetic influences in autism.

  "gap junctional communication in the olfactory epithelium modulates olfactory activity at the peripheral level and alters glomerular activation patterns (odor maps) in the olfactory bulb. Topological changes in odor maps due to gap junctional modulation could affect perception of odor quality or quantity." (Zhang)

To what extent do disruptions of Tregs contribute to disease development?

Many patients that have chemical sensitivity describe that the worst of the symptoms began occurring after a bout of infection. Multiple chemical sensitivity is a condition where symptoms such as nausea, respiratory problems, mood changes, cognitive problems and numerous other repored symptoms occur at a very low exposure of an "odor" stimulus. In the past, we have suggestedTreg impairment may be important for the development of many responses in MCS which may be long lasting or transient depending on factors including other secondary exposures that influence or prevent their activity. In addition, Treg disfunction has been implicated in a number of co-morbid health conditions such as inflammatory bowel disease and the sensitivities in autism. Interestingly, many common current treatments for MCS were used for treatments for autism before they were used for MCS.  Recent reports have also suggested that suppression of regulatory T cells from air pollution may be an important factor in the development and augmentation of respiratory disease like asthma. (Berkley) Air pollutants and particulate matter contain a variety of contaminants including LPS endotoxin from bacteria, hydrocarbons and metals. A recent study demonstrates that LPS a common contaminant of most environments can alter the expression of Cx43 and caveolin-3. The former Cx43 is a connexin protein that has been found to be important for the integrity of gap junctions shown to dictate olfactory sensitivity. Interestingly, regulatory T cells also play a role in the communication activities of gap junctions. Taking these recent studies into consideration the newest research on regulatory T cells in promotion of the adaptive response and maintaining tolerance support, one could propose that altered communication may play a role in chemical sensitivity and odor and olfactory function and prvode parallel support to the recent research of how Tregs disfunction may influence respiratory problems from air pollution. In addition, because their is a relationship gap functions to activity of NO/cGMP and its downstream targets and related biological roles in relation to memory -- this could explain some of the cognitive problems associated with MCS. Generally, suppression of Tregs and their role in gap function has implications for both animals and humans. In animals impairment of the olfactory system may negatively influence instinctual patterns of navigation and other behaviors.



Related: Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

****Read more research blogs: Kimberly Kramer
















Kay, Sharon. Memory and the Senses. New York University Physician. Spring 2010. Retrieved on October 1, 2010. webdoc.nyumc.org/nyumc/files/.../u3/NYUPhysSpring2010.pdf
The Logic of Smell. MedGadget, Internet Journal of Emerging Medical Technologies. Retrieved on October 14, 2010. http://medgadget.com/archives/2005/05/
BMC Neuroscience, Vol. 11, No. 1. (2010), 108. http://www.citeulike.org/user/HEIRS/article/7724812?show_msg=already_posted
Yang, Sarah. Air pollution alters immune function, worsens asthma symptoms. UCBerkelyNews.com. Retrieved on 10/13/2010.  http://www.berkeley.edu/news/media/releases/2010/10/05_asthma.shtml
Ring, S., Karakhanova, S., Johnson, T., Enk, A. H., and Mahnke, K. (2010). Gap junctions between regulatory t cells and dendritic cells prevent sensitization of cd8(+) t cells. The Journal of allergy and clinical immunology, 125(1). http://www.citeulike.org/user/HEIRS/article/8006437
Bopp, T., Radsak, M., Schmitt, E., and Schild, H. (2010). New strategies for the manipulation of adaptive immune responses. Cancer Immunology, Immunotherapy, 59(9):1443-1448. http://www.citeulike.org/user/HEIRS/article/6973883
Yao, J., Hiramatsu, N., Zhu, Y., Morioka, T., Takeda, M., Oite, T., and Kitamura, M. (2005). Nitric oxide-mediated regulation of connexin43 expression and gap junctional intercellular communication in mesangial cells. Journal of the American Society of Nephrology : JASN, 16(1):58-67. http://www.citeulike.org/user/HEIRS/article/8006401
González-Flores, O., Beyer, C., Lima-Hernández, F. J. J., Gómora-Arrati, P., Gómez-Camarillo, M. A., Hoffman, K., and Etgen, A. M. (2007). Facilitation of estrous behavior by vaginal cervical stimulation in female rats involves alpha1-adrenergic receptor activation of the nitric oxide pathway. Behavioural brain research, 176(2):237-243. http://www.citeulike.org/user/HEIRS/article/8006383
Lowe, G., Buerk, D. G., Ma, J., and Gelperin, A. (2008). Tonic and stimulus-evoked nitric oxide production in the mouse olfactory bulb. Neuroscience, 153(3):842-850. http://www.citeulike.org/user/HEIRS/article/8006357
Liao, C.-K. K., Wang, S.-M. M., Chen, Y.-L. L., Wang, H.-S. S., and Wu, J.-C. C. (2010). Lipopolysaccharide-induced inhibition of connexin43 gap junction communication in astrocytes is mediated by downregulation of caveolin-3. The international journal of biochemistry & cell biology, 42(5):762-770. http://www.citeulike.org/user/HEIRS/article/6580463
Kawasaki, A., Hayashi, T., Nakachi, K., Trosko, J. E., Sugihara, K., Kotake, Y., and Ohta, S. (2009). Modulation of connexin 43 in rotenone-induced model of parkinson's disease. Neuroscience, 160(1):61-68. http://www.citeulike.org/user/HEIRS/article/7971659
Zhang, C. (2010). Gap junctions in olfactory neurons modulate olfactory sensitivity. BMC neuroscience, 11(1):108+. http://www.citeulike.org/user/HEIRS/article/7724812

Li, D.-q., Li, X.-j., Duan, J.-f., and Cai, W. (2010). Wuling capsule promotes hippocampal neurogenesis by improving expression of connexin 43 in rats exposed to chronic unpredictable mild stress. Journal of Chinese Integrative Medicine, 8(7). http://www.citeulike.org/user/HEIRS/article/7971605

Effects of Exposure to Decabromodiphenyl Ether on the Development of the Immune System in Rats

Postnatal Day 77, levels of Tregs were decreased. This says to me that in animal exposed at an early age to DBPE may have reduced tolerance to environmental exposures as they age. So my question is...if there is a another point of elevated neural development such as would occur after injury does this kind of sensitivity also occur?

CiteULike: Effects of Exposure to Decabromodiphenyl Ether on the Development of the Immune System in Rats: "Teshima, R., Nakamura, R., Nakamura, R., Hachisuka, A., Sawada, J.-i., and Shibutani, M. (2008). Effects of exposure to decabromodiphenyl ether on the development of the immune system in rats. Journal of Health Science, 54(4):382-389."

Gulf War Syndrome, Chemical Sensitivity and Why Benefits of CPAP!

It has only been in the not-to-distant past that officials and medical experts have come out and admitted that Gulf War Syndrome is an actual disease and while many that have tried to find the cause the "true cause" is not yet known. In previous blogs, I have discussed how Gulf War Syndrome shares many of the same symptoms as other environmental conditions and are often co-morbid and include chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity and other environmental factors may contribute to fascilitate the condition that is commonly regarded as Gulf War Syndrome. One well-respected research blogger, Dr. Art Ayers, explains that CFS, MCS and fibromyalgia "can be induced by organophosphate pesticide exposure. In GWS, two insults seem to be needed: acetylcholine signal disruption and inflammation. He says that in the effected individuals the acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation." Without a clear understanding of what causes GWS, physicians and health experts are mostly at a loss on how to treat it and clearly, most of the research is now focused on providing effective therapies until a cure is found for it.

In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin)  While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.

To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation."  Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to  treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS."  If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.

Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain  fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP .  We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)

In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease.  (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)

Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown,  "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels  in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well.  (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)

I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl)  and supports that the AhR modulates Treg production (Mezrich) and they may  be a factor at least in some types of reactions to certain toxins.  It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.

As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis.  Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS.  Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue.  He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires".  This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff)  They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.

Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment.  The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis.  Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular."  In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)

Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan)  This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).

An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and  suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of  pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity.  The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)

I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of  GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so!  One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.





Amin, M. M., Belisova, Z., Hossain, S., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). Inspiratory airflow dynamics during sleep in veterans with gulf war illness: a controlled study. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756111
Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. (2004). Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep, 27(3):459-466. http://www.citeulike.org/user/HEIRS/article/7756324
Omurtag, G. Z., Tozan, A., Sehirli, A. O. O., and Sener, G. (2008). Melatonin protects against endosulfan-induced oxidative tissue damage in rats. Journal of pineal research, 44(4):432-438.  http://www.citeulike.org/user/HEIRS/article/2674835
Gulati, K., Banerjee, B., Lall, S. B., and Ray, A. (2010). Effects of diesel exhaust, heavy metals , and pesticides on various organ systems: Possible mechanisms and strategies for prevention and treatment. Indian Journal of Experimental Biology, 48:710-721. http://www.citeulike.org/user/HEIRS/article/7753532
Calero, G., Farre, R., Ballester, E., Hernandez, L., Daniel, N., and Montserrat Canal, J. M. (2006). Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome. Respiratory medicine, 100(5):813-817. http://www.citeulike.org/user/HEIRS/article/7756347
Singh, A. K. and Jiang, Y. Lipopolysaccharide (lps) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicology and Industrial Health, 19(2-6):93-108. http://www.citeulike.org/user/HEIRS/article/7796
Li, R., Ning, Z., Cui, J., Yu, F., Sioutas, C., and Hsiai, T. (2010). Diesel exhaust particles modulate vascular endothelial cell permeability: implication of zo-1 expression. Toxicology letters, 197(3):163-168.  http://www.citeulike.org/user/HEIRS/article/7284279
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D., and Rudich, A. (2010). Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology, 151(9):4247-4256. http://www.citeulike.org/user/HEIRS/article/7752881
Budhiraja, R. and Quan, S. F. (2009). When is cpap an antihypertensive in sleep apnea patients? Journal of clinical sleep medicine : JCSM, 5(2):108-109. http://www.citeulike.org/user/HEIRS/article/7752952
Amin, M. M., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). The effect of nasal continuous positive airway pressure on the symptoms of gulf war illness. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756404
Hersoug, L.-G. G., Husemoen, L. L., Sigsgaard, T., Madsen, F., and Linneberg, A. (2010). Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults. Respirology (Carlton, Vic.), 15(6):993-1000.  http://www.citeulike.org/user/HEIRS/article/7582695
Hersoug, L.-G. G. and Linneberg, A. (2007). The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy, 62(10):1205-1213. http://www.citeulike.org/user/HEIRS/article/1640991
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., and Dosch, H.-M. M. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature medicine, 15(8):921-929. http://www.citeulike.org/user/HEIRS/article/5398151
El Solh, A. A., Akinnusi, M. E., Baddoura, F. H., and Mankowski, C. R. (2007). Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. American journal of respiratory and critical care medicine, 175(11):1186-1191.  http://www.citeulike.org/user/HEIRS/article/7756664
Burioka, N., Miyata, M., Fukuoka, Y., Endo, M., and Shimizu, E. (2008). Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (cpap). Chronobiology international, 25(5):827-834. http://www.citeulike.org/user/HEIRS/article/7748469
Steiropoulos, P., Kotsianidis, I., Nena, E., Tsara, V., Gounari, E., Hatzizisi, O., Kyriazis, G., Christaki, P., Froudarakis, M., and Bouros, D. (2009). Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32(4):537-543. http://www.citeulike.org/user/HEIRS/article/7756944
Lam, J. C. M. and Ip, M. S. M. Obstructive sleep apnea and the metabolic syndrome: Osa and insulin resistance. Medscape Today. http://www.citeulike.org/user/HEIRS/article/7765845
Gaurdiola, J., Matheson, P., Cavijo, L., Wilson, M., and Fletcher, E. (2001). Hypercoagulability in patients with obstructive sleep apnea. Sleep Medicine, 2(6):517-523. http://www.citeulike.org/user/HEIRS/article/7790684
Nichols, Denise. Original Hypercoagulation Study on Gulf War Veterans. (August 20, 2010) Veterans Today. http://www.veteranstoday.com/2010/08/20/original-hypercoagulation-study-on-gulf-war-veterans/
Salvador, Lourdes. CPAP Machine Improves Gulf War Illness Symptoms for Some. American Chronicle. http://www.americanchronicle.com/articles/view/180225
Espada, S., Rojo, A. I., Salinas, M., and Cuadrado, A. (2009). The muscarinic m1 receptor activates nrf2 through a signaling cascade that involves protein kinase c and inhibition of gsk-3beta: connecting neurotransmission with neuroprotection. Journal of Neural Chemistry, 110(3):1107-1119. http://www.citeulike.org/user/HEIRS/article/7791380
Mauck, B., Lucot, J. B., Paton, S., and Grubbs, R. D. (2010). Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice. Neurotoxicology. http://www.citeulike.org/user/HEIRS/article/7395495
Beurel, E. and Jope, R. S. (2010). Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience. http://www.citeulike.org/user/HEIRS/article/7264009
Jensen, B., Leeman, R., Schlezinger, J., and Sherr, D. (2003). Aryl hydrocarbon receptor (ahr) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study. Environmental Health: A Global Access Science Source, 2(1):16+. http://www.citeulike.org/user/HEIRS/article/3802484?show_msg=already_posted
Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfiel, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. The Journal of Biological Chemistry, 274(17). http://www.citeulike.org/user/HEIRS/article/7795717
Foster, G. E., Hanly, P. J., Ostrowski, M., and Poulin, M. J. (2007). Effects of cpap on cerebral vascular response to hypoxia in obstructive sleep apnea patients. Respiratory and Critical Care Medicine, 175(7):720-725. http://www.citeulike.org/user/HEIRS/article/7795723
Matson, C. W., Timme-Laragy, A. R., and Di Giulio, R. T. (2008). Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere, 74(1):149-154. http://www.citeulike.org/user/HEIRS/article/7795748
Neff, Jerry. Bioaccumulation in marine organisms: effect of contaminants from oil well produced water. 2004. Pg 241. http://books.google.com/books?id=ABIQ_FGKOZcC&lpg=PA241&ots=v-kRmNZQY5&dq=polyaromatic%20hydrocarbons%2Bhypoxia&pg=PA241#v=onepage&q&f=false
Li, Y. J. J., Takizawa, H., Azuma, A., Kohyama, T., Yamauchi, Y., Takahashi, S., Yamamoto, M., Kawada, T., Kudoh, S., and Sugawara, I. (2010). Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clinical immunology (Orlando, Fla.). http://www.citeulike.org/user/HEIRS/article/7730119?show_msg=already_posted
Hsu, H.-F. F., Tsou, T.-C. C., Chao, H.-R. R., Kuo, Y.-T. T., Tsai, F.-Y. Y., and Yeh, S.-C. C. (2010). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3t3-l1 cells. Journal of hazardous materials, 182(1-3):649-655. http://www.citeulike.org/user/HEIRS/article/7383158?show_msg=already_posted
Wahl, M., Guenther, R., Yang, L., Bergman, A., Straehle, U., Strack, S., and Weiss, C. (2010). Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression. Toxicology letters, 198(2):119-126. http://www.citeulike.org/user/HEIRS/article/7408849
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. Journal of immunology (Baltimore, Md. : 1950), 185(6):3190-3198. http://www.citeulike.org/user/HEIRS/article/7795863
Ho, P. P. and Steinman, L. (2008). The aryl hydrocarbon receptor: a regulator of th17 and treg cell development in disease. Cell Research, 18(6):605-608. http://www.citeulike.org/user/HEIRS/article/3709745

Green Tea Compound, Hypermethylation and Tregs In Allergy and Chemical Sensitivity!

Recent studies propose that environmental illnesses are caused from "loss of tolerance" and that alterations in T regulatory cells (Tregs) may be a important factor. A number of studies demonstrate health benefits from epigallocatechin gallate (EGCG) which is a compound found in green tea. Yun shows EGCG can enhance Tregs production and enhance expression of histone deacetylases while decreasing expression of NF-kappaB. It also has been shown to reactivate genes that have been silenced by hypermethylation and prevent these changes to subsequent passage to daughter cells by DNA methyltransferases. (Fang) Interestingly, CCL18 is a chemokine that is elevated in allergic patients and may contribute to the "loss of tolerance" because in normal patients it promotes the generation of normal normal Tregs but in allergic patients it does not and may
an increased prevalence for symptoms that are common with chemical sensitivity in allergic patients. In addition, other factors including the proper expression of the Nrf2 system and other pathways for antioxidant expression may mitigate the effects while impairments may exacerbate them. EGCG has been shown to act through Nrf2, although this may not be its only mode of action. In any event, EGCG may provide some therapeutic effects for these kinds of conditions.


Yun, J.-M. and Jialal, I. Effects of epigallocatechin gallate on regulatory t cell number and function in obese versus lean volunteers. FASEB.http://www.citeulike.org/user/HEIRS/article/7651808
Fang, M. Z. Z., Wang, Y., Ai, N., Hou, Z., Sun, Y., Lu, H., Welsh, W., and Yang, C. S. (2003). Tea polyphenol (-)-epigallocatechin-3-gallate inhibits dna methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer research, 63(22):7563-7570.
http://www.citeulike.org/user/HEIRS/article/3326104
Chang, Y., de Nadai, P., Azzaoui, I., Morales, O., Delhem, N., Vorng, H., Tomavo, S., Ait Yahia, S., Zhang, G., Wallaert, B., Chenivesse, C., and Tsicopoulos, A. (2010). The chemokine ccl18 generates adaptive regulatory t cells from memory cd4+ t cells of healthy but not allergic subjects. The FASEB journal. http://www.citeulike.org/user/HEIRS/article/7651843

Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.

"induction of functional Foxp3(+) iT(reg) cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iT(reg) cells could be induced in human autoimmune disorders."

Read more: CiteULike: Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.

:"Gandhi, R., Kumar, D., Burns, E. J., Nadeau, M., Dake, B., Laroni, A., Kozoriz, D., Weiner, H. L., and Quintana, F. J. (2010). Activation of the aryl hydrocarbon receptor induces human type 1 regulatory t cell-like and foxp3(+) regulatory t cells. Nature immunology."

Insulin B:9-23/IFA immunisation induces Tregs that control late-stage prediabetes in NOD mice through IL-10 and IFNgamma.

CiteULike: Subcutaneous insulin B:9-23/IFA immunisation induces Tregs that control late-stage prediabetes in NOD mice through IL-10 and IFNgamma.: "Fousteri, G., Dave, A., Bot, A., Juntti, T., Omid, S., and von Herrath, M. (2010). Subcutaneous insulin b:9-23/ifa immunisation induces tregs that control late-stage prediabetes in nod mice through il-10 and ifngamma. Diabetologia, 53(9):1958-1970."

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice.

CiteULike: Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice.: "systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies."

Regulatory T Cell (Tregs) Production Dependant on Methylation Modifications~!

Background: New report support that the balance of Tregs need to be maintained for suppression of immune functions that lead to autoimmune-type reactions including those that may be seen in diabetes, colitis and lupus. In previous blogs, I suggest that loss of Tregs may influence the development of chemical sensitivity through the loss of Treg suppression and "loss of tolerance" and has been suggested by other authors. In the past, I have also reviewed several research studies that identify how recent findings of aberrant methylation influence environmental disease including autism, endometriosis and PTSD.

Interesting the following study by Floess shows that epigenetic modifications must occur with immune cells for cells to develop into "suppressor-type" lineages of Tregs. Therefore, alterations in methylation may negatively influence the development of Treg cells and could cause or augment environmental disease. This also provides a mechanism for what appears an inheritability of environmental disease.

Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H.-D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A., and Huehn, J. (2007). Epigenetic control of the foxp3 locus in regulatory t cells. PLoS Biol, 5(2):e38+.
http://www.citeulike.org/user/HEIRS/article/1080288

The imbalance between regulatory and IL-17-secreting CD4+ T cells in lupus patients

"The present study indicates that active SLE appears to exist as an imbalance between Treg and Th17 cells. Correction of this Treg/Th17 imbalance may have therapeutic impact for patients with SLE."

Link: CiteULike: The imbalance between regulatory and IL-17-secreting CD4+ T cells in lupus patients:

CRH and Tregs in Autoimmunity: Possible Connections to Chemical Sensitivity~!

Background: In earlier posts we described how commensal bacteria in the gut regulates the induction of T regulatory cells called Tregs that are important for immune functions. The loss of which may include autoimmune-type expressions and may be influential in MCS by loss of tolerance. In addition, we have also discussed how cortico-releasing hormone (CRH or CRF) has many effects and tissue targets, can be influenced by odors, may influence addictive-type behaviors and abherrant signaling may lead to altered signaling that can lead to mood disorders and have other negative influences on behaviors. The activation of CRH is part of the stress response and therefore, become an important part of the response to environmental cues. This same response activates the inflammatory cascade and therefore, the existence of one may coincide with the activation of the other. In addition, inflammatory cascades include activation of immune cells including mast cells.

Christy and Brown explain that Tregs are important in autoimmune disease and have the potential upon induction to prevent and reverse these conditions including diabetes and multiple sclerosis. Both of which are now considered to have an environmental connection. In addition the author notes that lupus, another condition with possible environmental triggers, and other autoimmune conditions are not just a loss of Tregs but a condition where other immune cells called Ag-effector cells become resistent to Treg suppression. At this point, one would suggest that other physiological pathways may be involved and this potentiates the non-adaptive conditions that lead to MCS. In other blogs, we have discussed a number of these conditions including nutrition and expression of cytokines, as well as, the expression of Nrf2.

Christy and Brown also present another important factor that very well may influence the development of MCS by contributing to loss of tolerance and that is the production of CRH from mast cells. These cells are often produced from inflammatory reactions such as those conditions that produced and reported from environmental toxin exposure. The authors discuss how the role of CRH produced from these inflammatory cells in basically an uptapped area of immune science. On the other hand, Soderholm does note that mast cells and CRH are implicated in disruptions of barrier function in irritable bowel syndrome and to a degree, it it now understood they are produced in inflamed tissue and increase inflammation. This protein has been implicated in reactions in rheumatoid arthritis and other inflammatory conditions during stress. For this reason, one can suggest that inflammatory conditions and production of mast cells which can produce this protein may contribute to the response and long-term activation can have important effects on downstream targets and participate in autoimmune-type response such as those observed in chemical sensitivities.

Past HEIRS Blogs: Related Tags: CRF , CRH , Nrf2


Christy, A. L. and Brown, M. A. (2007). The multitasking mast cell: Positive and negative roles in the progression of autoimmunity. J Immunol, 179(5):2673-2679.
http://www.citeulike.org/user/HEIRS/article/7357936
McKay, D. M. (2005). Good bug, bad bug: in the case of enteric inflammatory disease does the epithelium decide? Memórias do Instituto Oswaldo Cruz, 100(s1):205-210.

http://www.citeulike.org/user/HEIRS/article/7357955
Teitelbaum, A. A., Gareau, M. G., Jury, J., Yang, P. C., and Perdue, M. H. (2008). Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress. Am J Physiol Gastrointest Liver Physiol, 295(3):G452-459. http://www.citeulike.org/user/HEIRS/article/7357961

Commensal Bacteria Induce Tolerance via Tregs and Anti-Inflammatory Cytokine in Gut~!

Background: It has been suggested that multiple chemical sensitivity may be a consequence of loss of tolerance and (Tregs) by the immune system. In addition, this condition may also influence other environmental illnesses as well. One would assume any environmental condition that disturbs the natural environment of the intestinal tract could lead to the potential for chemical sensitivity if this is true. Considering this to be true, anything that improves healthy gut flora and reduces inflammation may be of benefit to those who suffer from this condition.

"Bacteroides fragilis, directs the development of Foxp3(+) regulatory T cells (Tregs) with a unique 'inducible' genetic signature. Monocolonization of germ-free animals with B. fragilis increases the suppressive capacity of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3(+) T cells in the gut. We show that the immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis mediates the conversion of CD4(+) T cells into Foxp3(+) Treg cells that produce IL-10 during commensal colonization. Functional Foxp3(+) Treg cells are also produced by PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg induction and IL-10 expression"

Inducible Foxp3+ regulatory T-cell development by ... [Proc Natl Acad Sci U S A. 2010] - PubMed result:

View Similar Posts: Tregs

Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissuesand endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.

HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine


HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,

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Original Article and Citations:

Chemical stress induces the UPR stress response in olfactory neurons.

The results of a new study show chemical stress from environmental insults is a major and chronic activator of the unfolded protein response (UPR) in olfactory sensory neurons which includes activation of a number of genes. (Sammeta) Wipedia describes "UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation (genetics) and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to initiate programmed cell death (apoptosis). One author states about the UPR in other tissues, "ischemia, chemical hypoxia and mitochondrial genetic disease (genetic hypoxia) can also induce this response." (Cortopassi)



Activity of Nrf2 is also involved with the response of chemical exposures on the nasal system which I have noted at length may be altered by a number of factors including hormone levels, ageing, nutrition,genetic factors, etc. As this article notes, the UPR response can become independant of odor-evokation and induce a loss of the enzyme CYP2A5 and REG3g. Notably, continuous activation of the UPR can alter signaling via the protein PERK through Nrf2. In 2003 Piras demonstrated that "CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region." In these findings, and because changes occurred in region that are analagous to neural glia which are active in neuroinflammation, future studies may show that changes in this area also induce neuroinflammatory responses without changes in Nrf2 levels. This study also noted alteraction in the abundance of the lectin called Reg3g....Several studies show this protein serves a homeotstatic function and this becomes important because the reduction of this lectin which kills gram (+) in the intestinal tract increases susceptibility to the effects of bacteria and includes changes in TLR signaling which may alter resistance to factors that lead to environmental disease in addtion to bacterial infection. The study of Reg3g is just begining and I am sure more studies will further clarify its role in nasal epithelia. From what has been observed thus far, this protein has been shown to have anti-diabetic properties and also may be regulated through a WNT pathway. Both of which, I have mentioned previously may influence autoimmunity, ammonia metabolism and other physiological effects that impact environmental illness especially in MCS and CFS.

You can read more about the Unfolded Protein Response here:


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Piras, E., Franzen, A., Fernandez, E. L., Bergstrom, U., Raffalli-Mathieu, F., Lang, M., and Brittebo, E. B. (2003). Cell-specific expression of cyp2a5 in the mouse respiratory tract: Effects of olfactory toxicants. J. Histochem. Cytochem., 51(11):1545-1555.
http://www.citeulike.org/user/HEIRS/article/6948536

Sammeta, N. and McClintock, T. S. (2010). Chemical stress induces the unfolded protein response in olfactory sensory neurons. The Journal of comparative neurology, 518(10):1825-1836.
http://www.citeulike.org/user/HEIRS/article/6873277?show_msg=already_posted

Kinnebrew, M. A., Ubeda, C., Zenewicz, L. A., Smith, N., Flavell, R. A., and Pamer, E. G. (2010). Bacterial flagellin stimulates toll-like receptor 5-dependent defense against vancomycin-resistant enterococcus infection. The Journal of infectious diseases, 201(4):534-543.
http://www.citeulike.org/user/HEIRS/article/6533280

Castellarin, M. L., Petropavlovskaia, M., Lipsett, M. A., and Rosenberg, L. (2007). The identification and sequence analysis of a new reg3gamma and reg2 in the syrian golden hamster. Biochimica et biophysica acta, 1769(9-10):579-585 http://www.ncbi.nlm.nih.gov/pubmed/17673309 .

Bluestone, J. A. and Hebrok, M. (2008). Safer, longer-lasting regulatory t cells with β-catenin. Nature Medicine, 14(2):118-119.
http://www.citeulike.org/user/HEIRS/article/2350828

Wipedia. Unfolded Protein Response. Retrieved on April 4, 2010. http://en.wikipedia.org/wiki/Unfolded_protein_response
 
Cortopassi, G., Danielson, S., Alemi, M., Zhan, S. S., Tong, W., Carelli, V., Martinuzzi, A., Manzuki, S., Majamaa, K., and Wong, A. (2006). Mitochondrial disease activates transcripts of the unfolded protein response and cell cycleand inhibits vesicular secretion and oligodendrocyte-specific transcripts. Mitochondria, 6:161-175. http://www.citeulike.org/user/HEIRS/article/6948589
 

Ammonia Enzymes, Immune Cells & X-Linked Mutations In Autoimmunity and Disease

Background: We have suggested that environmental illnesses may involve the loss of suppression of regulatory T cells and that several different proteins may be involved which changes the dynamics or "immunological footprint" of these conditions in each individual. Previously we mentioned how high ammonia levels may account for some of the symptoms associated with multiple chemical sensitivity. We also noted recently how alterations in ornithine enzymes may effect ammonia levels and the Nrf2 gene regulator has some control over its expression. The following article discusses findings related to how a mutation in ornithine transcarbamalase may influence the immune system and play a role in autoimmune type disease. Interestingly, the author points out the condition is X-linked which might account for higher number of females presenting with them because males usually die in utero and do not live but a few days after birth. There is usually a large sexual dimorphism in the prevalence of many environmental diseases. As Li explains, there may be a number of factors that contribute to autoimmune disease which may include estrogenic production as well as, vulnerable phenotypes may be more susceptible to metals exposure which may accelerate some individuals to reactive phenotypes. (Li)

The author writes, "Antigen expression in the thymus leads to the deletion of self-reactive T cells and generation of regulatory lymphocytes, including regulatory T cells(Treg) and NKT cells. We show an Ornithine transcarbamylase(OTC) mutation causes ineffective presentation of self antigens in the thymus. As such, deletion of self reactive T cells is compromised and production of Treg and NKT cells is reduced in the OTC mutant mice. More importantly the heterozygous mice have increased susceptibility to autoimmune diseases, including the generation of autoantibodies and more severe EAE." Further, "OTC mutant mice, the production of Treg in the thymus is reduced, which is correlated with the impaired antigen presentation due to hyperammonemia."


Comment: This article is a good representation of why only qualified medical professionals that understand the multitude of genetic conditions and environmental conditions that activate them should be treating them. There is no evidence thus far, that a "therapeutic recipe" is effective at treating all of them.


Chang, X. (2006). X linked foxp3 & otc in immune tolerance and autoimmunity. Ohio State University. http://www.citeulike.org/user/HEIRS/article/6650098
Li, J., Stein, T. D., and Johnson, J. A. (2004). Genetic dissection of systemic autoimmune disease in nrf2 deficient mice. Physiological Genomics.
http://www.citeulike.org/user/HEIRS/article/6604948

Regulatory T Cells and Inflammation in the Intestinal Tract

Background: It has been proposed that environmental pollutants may dysregulate Treg suppressive function and may therefore contribute to environmental illness.

"The enterocolitis in the Il10–/– mice is largely attributed to dysfunctional Tregs. As in many other models of intestinal inflammation, the inflammatory response in the intestinal mucosa in this model of colitis depends on luminal bacteria and/or their inflammatory components....In addition, this author reported that mice that were null for both IL10 and TLR4 have increased inflammation and is similar to the findings of increased inflammation from Helicobacter in Il10 -/- and TLR4 -/- animals. These findings suggest a positive role of TLR4 on the regulatory function of Tregs in intestinal inflammation."


González-Navajas, J. M., Fine, S., Law, J., Datta, S. K., Nguyen, K. P., Yu, M., Corr, M., Katakura, K., Eckman, L., Lee, J., and Raz, E. (2010). Tlr4 signaling in effector cd4+ t cells regulates tcr activation and experimental colitis in mice. Journal of Clinical Investigation.
http://www.citeulike.org/user/HEIRS/article/6488590?show_msg=already_posted

Tregs, Il17 and the C5a receptor -- MOA in Chemical Sensitivity????

Background: Here is an addition to something I noted before...or at least postulated that resveratrol may have some interesting immune effects...and lately I have suggested that a loss of tolerance by alteration in T regulatory cells may have important implications in multiple chemical sensitivity.

The activation of cellular pathways can have both positive and negative inflammatory influence. As Ward describes, "C5a and is an extremely potent pro-inflammatory peptide that interacts with two C5a receptors, C5aR and C5L2, present on surfaces of phagocytes as well as other cell types. The former is a well-established receptor that initiates G-protein-coupled signaling via mitogen-activated protein kinase pathways. Its in vivo blockade greatly reduces inflammatory injury." We wrote last year that resveratrol has been demonstrated to have a somewhat mitigating effect on anaphylatoxin (C5) neutraphils in peritonitis that included a decrease in a number of immune indicators such as Tnf-a, Il-6, Il-1 etc. and are often upregulated in Nrf -/- mice. Generally, another study indicated how mast cells may amplify immune responses in allergic disease and that C5ar may be an important mechanism in mast cell pathologies. Most recently studies reveal the absense of C5a receptors in dendritic cells regulates the immune response through promotion of T regulatory cells and Th17.

Issuree, P. D. A., Pushparaj, P. N., Pervaiz, S., and Melendez, A. J. (2009). Resveratrol attenuates c5a-induced inflammatory responses in vitro and in vivo by inhibiting phospholipase d and sphingosine kinase activities. FASEB J., 23(8):2412-2424. http://www.citeulike.org/user/HEIRS/article/5338821
Soruri, A., Grigat, J., Kiafard, Z., and Zwirner, J. (2008). Mast cell activation is characterized by upregulation of a functional anaphylatoxin c5a receptor. BMC Immunology, 9:29+. http://www.citeulike.org/user/HEIRS/article/2904779
Weaver, D. J., Reis, E. S., Pandey, M. K., Köhl, G., Harris, N., Gerard, C., and Köhl, J. (2010). C5a receptor-deficient dendritic cells promote induction of treg and th17 cells. European Journal of Immunology, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6614046
Thimmulappa, R. K., Lee, H., Rangasamy, T., Reddy, S. P., Yamamoto, M., Kensler, T. W., and Biswal, S. (2006). Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. The Journal of clinical investigation, 116(4):984-995.
http://www.citeulike.org/user/HEIRS/article/3716756?show_msg=already_posted
Czermak, B. J., Sarma, V., Bless, N. M., Schmal, H., Friedl, H. P., and Ward, P. A. (1999). In vitro and in vivo dependency of chemokine generation on c5a and tnf-alpha. J Immunol, 162(4):2321-2325.
http://www.citeulike.org/user/HEIRS/article/6614341
Ward, P. A. (2009). Functions of c5a receptors. Journal of molecular medicine (Berlin, Germany), 87(4):375-378.
http://www.citeulike.org/user/HEIRS/article/4012763

Antidepressants and Effects on Dopamine Receptors

"From our findings, we propose that the antidepressant drugs tested enhance dopamine function in the nucleus accumbens through either increased expression of postsynaptic D2 receptors (fluoxetine and desipramine) or increased dopamine release (tranylcypromine). "


SpringerLink - Journal Article: "Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat"

Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide.

In a preceding blog, we discussed how FOXP3 in important for autoimmune suppressing T cells. We also described how a recent study suggests that the loss of Tregs may be a contributing factor in chemical sensitivity and environmental illnesses from exposures to air contaminants. Here we see that NO is a factor in the altered expression in FOX3P Tregs.


CiteULike: Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide.: "Brahmachari, S. and Pahan, K. (2010). Myelin basic protein priming reduces the expression of foxp3 in t cells via nitric oxide. Journal of immunology (Baltimore, Md. : 1950)."

Discovery Of Compounds That Help Protect Nerve Cells

Last week we wrote about heat shock proteins could elevate Tregs - a class of T cells that help suppress autoimmune-like responses. We also discussed how these proteins may play a protective role against PD. Here is more on new discoveries on heat shock factor which induces the proteins.

Discovery Of Compounds That Help Protect Nerve Cells