CiteULike: NF-kappaB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells.

The suggests existence of a molecular CO(2) sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation.

CiteULike: NF-kappaB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells.: "Cummins, E. P., Oliver, K. M., Lenihan, C. R., Fitzpatrick, S. F., Bruning, U., Scholz, C. C., Slattery, C., Leonard, M. O., McLoughlin, P., and Taylor, C. T. (2010). Nf-kappab links co2 sensing to innate immunity and inflammation in mammalian cells. Journal of immunology (Baltimore, Md. : 1950)."

Regulatory T cells activity is potentiated by glycogen synthase kinase 3beta inhibition.

Comment: It has been suggested that chemical sensitivity and other conditions related to other environmentally-induced syndromes are a consequence of "loss of tolerance" which may be attributed to a reduction in the production of regulatory T cells that can suppress autoimmune responses and also may help in glucose homeostatic regulation. GSK-3b is similar to the on/off switch for the antioxidant system and is upregulated in inflammatory conditions.  Insulin and exercise have been shown to inhibit GSK-3b and other studies report that inhibiting GSK-3b may also reduce Il-6.

"Inhibition of GSK-3beta leads to increased suppression activity by Tregs."

CiteULike: Suppressive Treg cell activity is potentiated by glycogen synthase kinase 3beta inhibition.:

Related: GSK-3b

Meth Labs, Wood Treatments, Pesticides and Ammonia Toxicity on Astrocytes~!

Astrocytes: (astroglia) : are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a principal role in the repair and scarring process of the brain and spinal cord following traumatic injuries. (Wipedia: Astrocytes)

This study would suggest that any condition that impairs the antioxidant system which has a primary role in protecting astrocytes against damage (ie Nrf2)  would augment the toxicity of ammonia whether it be produced endogenously or from exogenous exposures. Young children, the elderly and those with impaired immune systems would also be more at risk. Products that contain ammonia or have it as an "inert" ingredient or exposures from hazardous environments such as methamphetamine labs pose an elevated risk for the above populations because they would be more susceptible to ammonia toxicity.

"This study demonstrated that in rats with HA or HE ammonia specifically promote GSH synthesis and export from astrocytes and increase its extracellular degradation, which may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity."

Hilgier, W., Wegrzynowicz, M., Ruszkiewicz, J., Oja, S. S., Saransaari, P., and Albrecht, J. (2010). Direct exposure to ammonia and hyperammonemia increase the extracellular accumulation and degradation of astroglia-derived glutathione in the rat prefrontal cortex. Toxicological sciences : an official journal of the Society of Toxicology, 117(1):163-168. http://www.citeulike.org/user/HEIRS/article/7292948?show_msg=already_posted
 
 

Vitamin D may treat and prevent allergic reaction to mold in cystic fibrosis patients

Comment: The following study helps support the HEIRS and others' hypothesis that MCS and other environmental illnesses are a "loss of tolerance" which involves impaired Treg production.


"PITTSBURGH, Aug. 25 – Vitamin D may be an effective therapy to treat and even prevent allergy to a common mold that can cause severe complications for patients with cystic fibrosis and asthma, according to researchers from Children's Hospital of Pittsburgh of UPMC, the University of Pittsburgh School of Medicine and Louisiana State University School of Medicine."

Read more: Vitamin D may treat and prevent allergic reaction to mold in cystic fibrosis patients:

For further reading: Tregs, loss of tolerance, FoxP3
     **********You can also search the HEIRS Citation database for related citations.


Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. Journal of immunology (Baltimore, Md. : 1950), 181(12):8650-8659.   http://www.citeulike.org/user/HEIRS/article/3752381

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 {beta}-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine

Background: It has been suggested that environmental illnesses such as chemical sensitivity entails a "loss of tolerance". Interestingly, it has also been proposed that the condition also be associated with inflammation in the gut and supports claims that it often develops after infection. Endotoxin activates the protein GSK-3b which has been shown to negatively influence the activities of beta-catenin and also the Nrf2. A new study by Manicassamy et al supports the necessity for beta-catenin in the development of tolerogenic dendritic cells. Another important note is the role of DISC1 which has been implicated in a number of mental disorders and subset of chronic fatigue syndrome inhibits GSK-3b activity. The beta-catenin pathway is also responsible for toxin removal of ammonia.


Activation of {beta}-Catenin in Dendritic Cells Re... [Science. 2010] - PubMed result: "Activation of {beta}-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine."

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

Listen and Learn About Chemical Sensitivity

Listen and learn about chemical sensitivity. An audio interview by Dr. Lynn Marsall of Canada.

Is This a Plausible Mechanism for Multiple Chemical Sensitivity Responses?

The results of this study suggest that "electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape, defensive behavior that has been related to panic attacks and that serotonin signaling may influence the panic behavior."

"Considering the triggers, this seems like a very plausible explanation for the mechanism or something similar in multiple chemical sensitivity. This area seems to be influenced by stress signalling and also interacts with certain proteins including the CRH which reacts to environmental cues that leads to changes in neurotransmission. According to one source, "periaqueductal gray matter is responsible for inhibiting nociceptive activity (often leading to pain) though the release of certain proteins. Nociceptive signaling forms a platform for the "central sensitization" in fibromyalgia and other pain conditions and involves the enhancement of impulses and dysfunction in the pain system." For this reason, it very well could be an important component in the responses associated with chemical sensitivity.(Spaeth) As far as fibromyalgia, alterations in serotonin have been noted in past studies.


CiteULike: Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter.: "Miguel, T. L. B. L., Pobbe, R. L. H. L., Junior, A. S. S., and Junior, H. Z. Z. (2010). Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter. Behavioural brain research."





Sources:
The Neurochemical Response Patterns to Acute Stress. Retrieved on May 13, 2010. http://focus.psychiatryonline.org/cgi/content/full/2/3/368/T1
Spaeth, M. (2006). Fibromyalgia syndrome: The role of neurochemicals. Primary Psychiatry, 13(9):72-75.
http://www.citeulike.org/user/HEIRS/article/7167665

Individual Responses to Volatile Contaminants Are Influenced By Genetic Makeup

Definition:
Aerosol:suspension of fine solid particles or liquid droplets in a gas. Examples are smoke, oceanic haze, air pollution, smog and CS gas. The word aerosol derives from the fact that matter "floating" in air is a suspension. (Wipedia)
Particulate Matter: are tiny subdivisions of solid or liquid matter suspended in a gas or liquid.
Redox potential (reduction potential): a tendency of a chemical species to acquire electrons and thereby be reduced.
Electrophile: electron lover- a substance that accepts an electron pair. Carbonyls and acids are examples.
quinone: a class of organic compounds that are formally derived from aromatic compounds.


Background: In other blogs, we have explained how particulate matter is a health hazard and the smaller or more fine the particulate the more likely it is to cause a heightened inflammatory response. There are several reasons for this but two important ones are because they have a larger surface area to bind with other contaminants and they are small enough to reach the deeper part of the lungs (if inhaled) or digestive tissue (if ingested) and infiltrate lower levels of tissue where they increase inflammation. Recently, a study of mice demonstrated how different strains have different basal levels of antioxidant genes that could potentially cause a increased or decreased risk for health consequences. In this case, it was a model for COPD which is an inflammatory respiratory disease and cigarette smoke. One can conclude from the results of this study and if the same is true for humans as it is for mice, different ethnic groups, lineages, etc. may be more susceptible than others to environmental contaminants. Interestingly, different mouse strains exhibit differences in basal levels of proinflammatory cytokines, oxidative stress and also expression of antioxidant genes Nrf2, HO-1, glutathione and others including IL-6. (Vecchio) These results augment controversial findings that suggest infections are less environmental than they are genetic and a person's susceptibility and ability to recover has to do less with environmental factors than it does genetics. (EurekAlert)

A few new studies shed a little bit more light on the chemical properties of PM and provides support for the idea that "semi-volatile and volatile contaminants have been implicated in causing adverse health effects. From this study, the author examined hazard levels in regards to the particle or vapor in an aerosol. He explains that redox-active components are particle-phase and vapors are more electrophilic and noted that latter contaminants were capable of inducing HO-1, a strong antioxidant and stress response protein. From this he concluded that volatile properties should be considered when determining the hazardous nature of a contaminant." While this may seem like greek to some, a general conclusion one can make from this is volatile properties of contaminants have adverse health effects. In addition, an investigator must be cognizant and consider genetic expression may influence a person's immune response to environmental contaminants including those that are volatile vapors.

Comment: The findings of these studies should have important influence on treatments descisions for MCS patients.


Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology. http://www.citeulike.org/user/HEIRS/article/6675046?show_msg=already_posted
Eiguren-Fernandez, A., Shinyashiki, M., Schmitz, D. A., Distefano, E., Hinds, W., Kumagai, Y., Cho, A. K., and Froines, J. R. (2010). Redox and electrophilic properties of vapor- and particle-phase components of ambient aerosols. Environmental research. http://www.citeulike.org/group/7769/article/6704033
(2010). Rockefeller scientist to speak at aaas on infections as genetic disorders.
http://www.citeulike.org/user/HEIRS/article/6704247
Shinyashiki, M., Eiguren-Fernandez, A., Schmitz, D. A., Di Stefano, E., Li, N., Linak, W. P., Cho, S.-H. H., Froines, J. R., and Cho, A. K. (2009). Electrophilic and redox properties of diesel exhaust particles. Environmental research, 109(3):239-244. http://www.citeulike.org/group/7833/article/6705178

Ammonia, ASIC Channels and Mental Health

We recently have been discussing how the biological accumulation of ammonia may be an important condition related to a number of environmental illnesses. In fact, several studies suggest that accumulation of ammonia may contribute to autism and others note it plays a very important role in hepatic failure. As we noted, elevated levels of homocysteinemia may impair the urea cycle - which helps the body get rid of excess ammonia and glutamine synthetase genes of the Wnt/Catenin pathway, also regulate  ammonia concentrations in the body. Interestingly, several "so-called therapies" for MCS also have the capacity to reduce ammonia. Also, it is well-known that psychological disturbances are co-morbid with a number of environmental conditions, in addition to those mental effects associated with autism and liver disease.

In light of the potential for elevated ammonia levels to influence the psychological and physical effects of environmental disease, I thought I would point out two interesting studies. The first is a study that suggests that ASIC channels contribute to the health consequences where hyperammonemia becomes an issue. As the author points out, this may include hepatic encephalopathy, cirrhosis and neuronal disorders. This study discusses how these types of channels have been implicated in neuronal death after their activation. Incidentally, nociceptive behavior is associated with acidic environments that develop from injury and inflammation and therefore could play a role in the pain generation in environmental illnesses including  MCS (Pall) and chronic fatigue syndrome (Light).  Pidoplichko provides evidence the involvement of these channels may contribute to the loss of dopamine neurons in Parkinson's disease because these channels are associated with those neurons and "ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus." The second study seems to suggest that these same channels have an important role in the development of depression-related behavior by demonstrating genetically altered -/- mice presented with anti-depressant-like behaviors even while put under experiemental stress. In addition, the dysruption of these channels interfered with an important "biomarker of depression" which is a decrease of levels of BDNF in the hippocampus. In past blogs, we have explained how BDNF is important for "olfactory neurogenesis" and may be important consideration in the development of MCS.  Coryell concludes by saying that his "findings of ASIC1 signaling in the amydala in mood regulation support others and that pharmaceutical approaches that target ASIC1 signaling may be therapeutic for this kind of depression. We might propose that investigating therapies that reduce ASIC signaling may be beneficial for a number of environmentally-related conditions may be of value.

Notes:

• A recent study shows that HO-1 activates bilirubin and CO to modulate BDNF/GDNF in neurons and astrocytes. This provides a protective effect on dopaminergic neurons.

Coryell, M. W., Wunsch, A. M., Haenfler, J. M., Allen, J. E., Schnizler, M., Ziemann, A. E., Cook, M. N., Dunning, J. P., Price, M. P., Rainier, J. D., Liu, Z., Light, A. R., Langbehn, D. R., and Wemmie, J. A. (2009). Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J. Neurosci., 29(17):5381-5388. http://www.citeulike.org/user/HEIRS/article/6607146
Pidoplichko, V. I. and Dani, J. A. (2006). Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proceedings of the National Academy of Sciences of the United States of America, 103(30):11376-11380. http://www.citeulike.org/user/HEIRS/article/6607127
Light, A. R., White, A. T., Hughen, R. W., and Light, K. C. (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The journal of pain : official journal of the American Pain Society. http://www.citeulike.org/user/HEIRS/article/5370052
Ugawa, S., Ueda, T., Ishida, Y., Nishigaki, M., Shibata, Y., and Shimada, S. (2002). Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. The Journal of clinical investigation, 110(8):1185-1190. http://www.citeulike.org/user/HEIRS/article/2942104
Pall, Martin (2007). Explaining Ünexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479
Hung, S.-Y. Y., Liou, H.-C. C., and Fu, W.-M. M. (2010). The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology, 58(2):321-329. http://www.citeulike.org/user/HEIRS/article/6196852

Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!

I recently discussed how IL-10 determines the severity and length of sickness syndrome. At that time, I suggested chemical sensitivity is a loss of tolerance caused by an imbalance of T regulator cells and dysfunction of Nrf2 and based this assumption on a recent study showing environmental pollutants may lead to a decrease in the expression of Tregs whereas, normally chronic exposure increases them. In previous animal studies, the loss of Tregs results in the development of "immediate autoimmune-type disease."

The paragraphs below will provide more support for the idea that Nrf2 does indeed play a role in environmental illness including MCS in particular. First of all, it is important to review that environmental illnesses usually include allergy, asthma, inflammatory bowel disease, diabetes, lyme disease, heavy metal disease, chemical sensitivity, just to name a few. Generally, environmental illnesses may be categorized as Th1 or Th2 according to their T cell pathway subset which is either considered to be cell-mediated or humoral , respectively. Vodjani provides a graphical representation of environmental illnesses in relation to autism in his article and classifies them as Th1 or Th2. He classifies chemical sensitivity as a Th2 humorally- regulated autoimmune disease along with allergy and asthma. Tregs, as he describes, are cells that try to negotiate a balance between cells that suppress and ones that maintain homeostasis. More simply, they are T cells with specific markers. Personally, I have dubbed them to be immune cell referees!

This is how he classifies the autoimmune diseases:

Th1 Autoimmune Disease

• mulptiple sclerosis
• diabetes
• arthritis
• uveitis
• lyme disease
• mercury-induced autoimmunity
• atopic dermatitis (initiation phase)
• inflammatory bowel disease
• bacterial infection
• mold infection

Th2 Autoimmune Disease

• lupus erythematosis
• lead-induced autoimmune disease
• allergy
• asthma
• chemical sensitivity
• parasitic infection
• atopic dermatitis (acute phase)
• inflammatory bowel disease
• bacterial infection
• malignancy

This author also describes the steps involved when conditions in the intestinal tract initiate autoimmune disease and brain disfunction/ neurodegeneration. These steps are as follows:

1. mucosal immune abnormalities
2. imbalanced gut flora
3. intestinal barrier diysfunction
4. systemic inflammation
5. neuroinflammation
6. neuroinvasion
7. neurodegeneration

In support of the idea of chemical sensitivity as an autoimmune disease one needs to understand the concept of loss of tolerance which include loss of Tregs and loss of suppression of inflammatory initiators. This loss may depend on other proteins such as Il-10 and HO-1 which are ultimately directed or indirectly regulated by Nrf2. For instance, it has been demonstrated Nrf2 -/- cells express lower HO-1 which is necessary for Treg suppression.  Tregs levels also are negatively influenced by high-fat (Ma), age, mental stress, are differentially regulated by different AhR ligands (Quintana) and vitamin D levels. The last of which also decreases with age.

Williams and his team provides more insight into how the expression of Nrf2 is different with exposure to environmental pollutants. This article is long and the author makes several points worth discussion that support the notion of the possible involvement of Nrf2 in chemical intolerance. Initially the researcher describes how Nrf2 deficiency may stimulate a Th2 response according to the type of pollutant such as particulate matter. He admits even after presenting his findings, exposures to mixed pollutants are hard to analyze but he believes he uses an approach to match a "real-world" setting. His findings provide a mechanism for how certain environments tend to be more reactive to certain people and why these reactions do not always "appear" to be allergenically-mediated. Through this study, the researcher demonstrates Nrf2 positive and Nrf2 deficient animals show different immune profiles when exposed to different pollutants. For example, he found IL-18 was increased in Nrf2 positive but decreased in Nrf2 deficiency. This suggests Nrf2 regulates Il-18 which plays a role in inhibiting IgE in B cells. Typically, IL-18  is associated with some types of allergy, most often bacterial or viral and curiously, it is elevated in chronic autoimmune urticaria (itchy rash). (Ibrahim) Also, Nrf2-/- show lower protein CD40 that regulate IgE response which may include mild allergy-type responses like in hay fever to life threatening symptoms of anaphylactic shock. Nrf2 levels can fluctuate and if alterations of CD40 and IgE reflect this, it may explain why IgE profiles are often "scewed" in MCS patients. Williams also demonstrated that NAC, a common antioxidant used in MCS therapy has both positive and negative immune effects depending on the type of exposure to the point it may influence the Th1 or Th2 subtypes and may explain why some patients have good luck with NAC therapy and others do not.  It also makes it evident that MCS treatments need to be medically-focused and individualized, why control of environmental stressors are critical and at least for the present, no "recipe" is going to be a "fix" for every MCS patient.

Williams states "oxidative stress is an important determinant of what path Th1 or Th2 autoimmunity takes and Nrf2 dysfunction may determine whether disease presentation is more of a Th1 or Th2 pattern." (This is an explanation for why patients with MCS have a long list of co-morbid health conditions and why they experience such a wide spectrum of symptoms.) Most importantly his findings demonstrate as he explains,  "In this elegant study it was shown that a change in the intracellular redox status of DCs upon activation by particulates such as diesel exhaust particulates disrupt the normal ability of TLR agonists to mature DCs and this perturbation of DC function was associated with dampened IFN- and augmented IL-10 secretion in Ag-specific T cells, agreeing with these Nrf2 findings. Our data supports the idea that restoring the oxidant/antioxidant balance in DCs may have a therapeutic benefit in Th2-dominant allergic diseases. Also, enhanced activation in Nrf2-/- exposure to PM may result from decreased expression of HO-1 which is a powerful immunosuppressive" which provides evidence of loss of Treg involvement. George et al findings indeed demonstrated that Treg suppression is dependant on HO-1. HO-1 defiency leads to abolished Treg cell suppression activity normally necessary for keeping the Th1 and Th2 immune balance responses "in check" .  Interestingly it seems, the contaminant and how effective the immune response to it ultimately may determine the development of MCS and how severe the symptoms if this author and the concept of "loss of tolerance" is attributable to the condition.  As we have noted, HO-1 regulates Il-10 which is involved in Treg regulation and with the loss of IL-10 and lower levels of Tregs, heightened reactions and inflammatory responses could occur. Supportively, the author explains, "Nrf2-disrupted DCs exhibit a heightened and constitutively proinflammatory state. These observations indicate an important role for Nrf2 in gauging an appropriate pattern of inflammatory activation of DCs, key regulators of the immune response, to danger signals such as environmental particulate matter or other allergens. Disruption of the Nrf2 gene may potentially enhance host susceptibility to various allergic or infectious diseases" and this he admits, "warrants further study."

 For further reading:

• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Williams, M. A., Rangasamy, T., Bauer, S. M., Killedar, S., Karp, M., Kensler, T. W., Yamamoto, M., Breysse, P., Biswal, S., and Georas, S. N. (2008). Disruption of the transcription factor nrf2 promotes pro-oxidative dendritic cells that stimulate th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol, 181(7):4545-4559. http://www.citeulike.org/user/HEIRS/article/3716629?show_msg=already_posted
Vojdani, A. and Lambert, J. (2009). A gut feeling for immune dysregulation & neuroinflammation in autism. http://www.citeulike.org/user/HEIRS/article/6498182
Definition of Dendritic Cell. MedicineNet.com. Retrieved January 7, 2009.
George, J. F., Braun, A., Brusko, T. M., Joseph, R., Bolisetty, S., Wasserfall, C. H., Atkinson, M. A., Agarwal, A., and Kapturczak, M. H. (2008). Suppression by cd4+cd25+ regulatory t cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol, 173(1):154-160 http://www.citeulike.org/user/HEIRS/article/6477829?show_msg=already_posted
Ibrahim, S. A. and Khalifa, N. A. (2009). Interleukin-18 correlates with disease severity in chronic autoimmune urticaria. Egyptian Dermatology Online Journal, 5(1). http://www.citeulike.org/user/HEIRS/article/6509891
Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529. http://www.citeulike.org/group/6096/article/6496762
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T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Over the past several months there has been a number of studies that shed light on the activities of a subset of immune cells called regulatory T-cells. Interestingly, these new findings may result in answering some important questions related to multiple chemical sensitivity which is a condition where patients become sensitive to agents normally found in the environment and these agents can be "natural" or manmade. Every MCS patient is different but their symptoms may include nausea, vertigo, brain fog, light sensitivity and others. Generally, reactions occur when MCS patients are exposed to concentrations of noxious stimulants, chemical agents or irritants that would not normally elicit a reaction in those without MCS. While there are many theories out there about what causes MCS, so far there are few that actually come close to understanding MCS and other facets of environmental illness. Unfortunately, many health experts are critical about the existence of MCS and try to classify it as a "psychomatic condition" while others are more open-minded and have begun to rally and now treat multiple chemical sensitivity as a "real" medical condition.

One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.

Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.

Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)

It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.

Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.




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