Particulate Matter in Pollution Exacerbates Environmental Illness via the Nrf2 Pathway!

In the past, I have made several post on particulate matter and how pollution may negatively influence the main environmental illnesses chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity. It is believe that what these conditions have in common is higher than normal oxidative stress and higher levels of inflammation. In addition, I believe that deficiencies in the Nrf2 pathway may exacerbate the conditions.

Through the discoveries from a study on dendritic cells, more has been learned about how Nrf2 and particulate matter interact to lessen or contribute to disease. Dendritic cells are an important part of the antigen-presenting immune system. The author writes that exposure to particulate matter in an Nrf2 deficient environment leads to 1) impairment of antigen endocytosis 2) significantly higher levels of oxidative stress probably due to lower levels of antioxidants like GCL and HO-1 3) higher levels of inflammatory cytokines including TNF-a and Il-6 4) lower levels of Il-18 4) less sensitivity to NAC and 5) Nrf2 deficiency may influence Th2 cytokine development leading to allergic diseases. (1)

This study provides clues to how particulate matter may influence the development of higher than normal levels of oxidative stress. People with conditions that already have conditions where these levels are higher should be aware that exposure to pollution indoors and outdoors may make their symptoms worse. In addition, we previously have written that many things can cause deficiency in the Nrf2 antioxidant pathway. This includes genetic factors, direct chemical exposure, changes to the microbiome and high fat diets.


1. Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter. Journal of immunology (Baltimore, Md. : 1950), Vol. 181, No. 7. (01 October 2008), pp. 4545-4559 by Marc A. Williams, Tirumalai Rangasamy, Stephen M. Bauer, et al.

Volatile Organic Compounds (VOC) Come from a Variety of Sources In the Home!

Volatile organic compounds (VOC) are all around us and are an inherent part of pollution. Recent studies show that a number of VOCs come from common household products like food, pesticides and shampoo. Read more....



Volatile Organic Compounds (VOCs) and Pollution. Jack Dini. Canada Free Press. March 14, 2018. https://canadafreepress.com/article/volatile-organic-compounds-vocs-and-pollution

Paraquat Produces Oxidative Stress in Dose-dependant Manner. Implications for Nrf2.

It was determined through a new study that exposure to dose dependent levels of Paraquat is responsive for increasing levels of oxidative stress. At lower level, production of oxidative stress was reduced by activation of the Nrf2. At higher dose levels, Nrf2 activation was inhibited which resulted in higher levels of oxidative stress and tissue damage.

This is important because Paraquat is an important agricultural herbicide that is used around the world. There are numerous reports that it crosses the blood brain barrier and accumulates in different brain regions. Because of this, it is believed that it does damage to dopamine neurons. It has also been found to cross the placenta and has been found in higher concentrations in the placenta than in the mother's blood. For this reason, the exposure to Paraquat may put a fetus at risk when the mother is exposed. In addition, Paraquat exposure has been linked to Parkinson's disease and Nrf2 inhibition at higher levels may to be blame for development of the disease. Of course, since oxidative stress is caused by exposure to Paraquat, people that have diseases or conditions where oxidative stress is a factor may be more negatively effected. (1)


Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells. Oxidative medicine and cellular longevity, Vol. 2016 (2016) by Tingting Dou, Mengling Yan, Xinjin Wang, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663008/

Protein Signalling From POPs: A Case for Environmental Illness!

Over the past several years, I have proposed that aberrant signalling from the AhR and the NRF2 may influence the development and chronicity of an environmental illness. Mant experts believe there is also chronic low-level inflammation that coincide with their development and continues through the course of conditions like MCS, CFS and fibromyalgia. In addition, I have made the case for the fact, that low-level inflammation from these conditions contributes to obesity which I also believe should be included under the umbrella of environmental illnesses. Mainly, because of the way low-level inflammation affects the adipocytes and because many environmental factors contributes to the development of obesity and as obesity progresses to the development of diabetes. I also point out several times, how the Western diet may contribute to environmental illnesses, especially as they become chronic and proceeds to last many months or years. Numerous studies in recent years have shed some light on adipocytes function and physiology. Many experts now consider the presence of healthy adipocytes as a necessary part of being healthy. The problems begin when low-level inflammation infiltrates the adipose tissue and leads to disease.
       As Greenburg and Obin point out, in 2001 the number of obese adults reached almost 21%. That statistic has grown to 34.9% of adults are obese adults in the U.S. alone. As the numbers of obese grow, obesity becomes more a more a public health issue. "Numerous diseases are considered to be either caused by obesity as the sole cause or in part caused by it. Just a few these include type-2 diabetes, cardiovascular disease, hypertension and stroke, hypercholesterolemia, arthritis, and certain cancers. Within the past few decades, more understanding of adipocytes has taken place. It is now known they are important metabolically. Their function is also dictated by a number of factors which include diet, exercise, hormones and genetics. Adipocytes play a role in controlling how much fat is deposited in important organs such as the liver and muscle, improving insulin sensitivity and decreasing triglycerides. They also regulate two important hormones, adiponectin and leptin.   Adiponectin is a hormone that regulates glucose tolerance and sensitivity. In addition, its levels are associated with type-2 diabetes and metabolic syndrome. On the other hand, leptin influences food uptake. In mice, missing the gene for leptin, exhibit extreme obesity and are diabetic. It also regulates fat mass.
     In individuals that are becoming obese, changes occur in adipocytes. Compared to their leaner counterparts, the obese have an inflammatory phenotype. In addition to TNF-a, they also produce higher levels of Il-6 and MCP-1. Macrophages increase with obesity and their presence is responsible for the production of TNF-a and a lot of IL-6. There is also a large increase in insulin. All of which decrease upon application of a diabetes drug. The inflammation also contributes to the downregulation of adiponectin which naturally  inhibits TNF-a." (Greenberg and Obin)
    In other blogs, I have explained that for those who suffer from environmental illnesses, it is important to clean up the gut. Recent studies show that there is a direct connection from the gut to the brain. I believe that many people that suffer from these conditions must be vigilant in how they eat and what they drink because the health of the gut depends on it. Again, let me mention that I also believe that aberrant signalling from the AhR and Nrf2 may contribute to environmental illness. At least in terms of  the AhR, Zhang et al states that the AhR plays an influential role in the gut and that role plays an important part in metabolism in obesity from persistent organic pollutants.  In a new study, Zhang and his colleague hypothesized that gut homeostasis is disturbed by exposure to persistent organic pollutants (POPS) through the diet and those exposures can lead to obesity. I must comment here that whether exposure to POPS or a Western diet leads to obesity, the process and the physiology is much the same as I described above. "During this study, 6 weeks old wild-type and mice that were AhR -/- were fed 2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental contaminant for 5 days. Several studies were done to assess how this contaminant affected the gut microbiome and what other effects presented themselves from exposure to the TCDF. At the end of the study, the researchers determined there was a change in the populations from more Firmicutes to Bacteriodetes. Both of which have metabolic responsibilities.  Also, TDCF-treated mice were enriched with Butyrivibrio but depleted in Oscillobacter and the change was associated with altered bile metabolism. Also, there was a significant increase in inflammation as a result of bacterial fermentation  and altering hepatic lipogenesis, gluconeogenesis and glycogenolysis, in an AHR-dependent manner. It is concluded that POPs alter signalling the AhR to affect changes in metabolism. Changes also occur simultaneously in the gut species that increase inflammation. " The author states that past studies have demonstrated that the AhR-Il22 impacts mucosa in the gut. In addition, dietary components and environmental contaminants alter gut homeostasis and leads to disease including obesity, diabetes, and inflammatory bowel disease. (Zhang)


For further reading: (there are more than those listed here)
Inflammation Can Cause Depression!
Health Consequences Can Be More Severe When Multiple Environmental Toxicant Exposures Occur at the Same Time! 


TLR4 Activity in the Gut Contributes to Symptoms in Chronic Fatigue Syndrome!

What is the NRF2 and Why is Food Better than Supplements?

Adult Obesity Facts. Centers for Disease Control and Prevention. http://www.cdc.gov/obesity/data/adult.html

Obesity and the role of adipose tissue in inflammation and metabolism American Journal of Clinical Nutrition, Vol. 83, No. 2. (February 2006), pp. 4615-4655 by Andrew S. Greenberg, Martin S. Obin. http://www.citeulike.org/user/kimberlykramer2015/article/13568522

Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation. Environmental health perspectives (13 March 2015) by Limin Zhang, Robert G. Nichols, Jared Correll, et al. http://www.citeulike.org/user/kimberlykramer2015/13565027

Nitric Oxide Synthase Might Be Used for Diagnosis of Environmental Illness!

"Genetic polymorphisms may explain what individual get what idiopathic environmental disease. The author of this new study demonstrates how he is able to differentiate patients with MCS, FM and CFS by genetic differences in nitric oxide synthase. He concludes that screening using NOS may be available and useful for diagnosis of disease." 

Role of polymorphisms of inducible nitric oxide synthase and endothelial nitric oxide synthase in idiopathic environmental intolerances. Mediators of inflammation, Vol. 2015 (2015) by Chiara De Luca, Agnese Gugliandolo, Carlo Calabrò, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13584669

Tregs and Immunosuppression in Environmental Illness!

 

      In the past several blogs, I have proposed that multiple chemical sensitivity may be due to the loss of Fox3p regulatory T cells  or Tregs which are negative regulators of inflammation. On one hand, several  studies over the past several years have demonstrated that the loss of immunosuppression from Tregs results in diseases like asthma or inflammatory bowel disease (Wang) But what about less common conditions like multiple chemical sensitivity (MCS) that seems to result in a "loss of tolerance"? Over the last six years, I have made a case for the aberrant signalling from the Nrf2 or AhR may also contribute to symptoms and Nrf2 activators which many are AhR ligands may be of benefit in relieving symptoms at least temporarily.  On the other hand, one author argued that patients exposed to less air pollution exhibited lower Tregs and that the increase or decrease of them could be useful in monitoring environmental disease. (Micovic)

     I found a few recent studies that are interesting as far as Treg suppression in relation to environmental disease. In one of these studies, Kohli found that a mixture of second hand smoke and ambient air pollution resulted in hypermethylation and decreased transcription of IFN-y and Fox3p Tregs. Passed studies show an association with a decrease of both of these proteins in asthma and allergic disease. Ambient air pollution, according to the author, is generally considered as "compounds that include polycyclic aromatic hydrocarbons (PAH), particulate matter that is less than 2.5 um (PM 2.5) , particulate matter less than 10um (PM10), carbon and ozone."

    Vallares has found that growth hormone (GH) stimulates T and B cell proliferation. In his study in autoimmune diabetes, he observed that consistent production of GH prevented the progression of pancreatic symptoms to overt autoimmune diabetes. This involved GH changing the cytokine environment and maintained a suppressor T cell (Treg) population.

    I have written several times about resveratrol, a phytochemical in wine, is an Nrf2 activator and might be a treatment for autoimmune disease like inflammatory bowel disease.  Recently Wang et al reported that resveratrol can inhibit inflammatory cytokines and relieve oxidative stress from a high-fat diet. Interestingly, resveratrol prevented the suppression of Tregs via the the aryl hydrocarbon receptor that is inhibited by high-fat diet. It seems that resveratrol not only stimulates Nrf2 but also acts through the AhR, and both of which I suspect could play a role in MCS. In addition, Busbee and Haniah write how AhR signalling may impact autoimmune disease by activating Fox3p Tregs and inhibiting or downregulating Th17. Haniah makes the comment that further study is needed but the AhR may prove to be a therapeutic strategy against autoimmune diseases.  Busbee notes that the AhR signals impact a number of genes, many of which I have discussed before and is present in a variety of tissue.  

       

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

T regulatory cells and B cells cooperate to form a regulatory loop that maintains gut homeostasis and suppresses dextran sulfate sodium-induced colitis. Mucosal immunology (25 March 2015) by L. Wang, A. Ray, X. Jiang, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13578157

Regulatory T cells (Tregs) monitoring in environmental diseases. Collegium antropologicum, Vol. 33, No. 3. (September 2009), pp. 743-746 by Vladimir Mićović, Bozo Vojniković, Aleksandar Bulog, et al. http://www.citeulike.org/user/kimberlykramer2015/article/6090770

Secondhand smoke in combination with ambient air pollution exposure is associated with increasedx CpG methylation and decreased expression of IFN-γ in T effector cells and Foxp3 in T regulatory cells in children. Clinical epigenetics, Vol. 4, No. 1. (2012), doi:10.1186/1868-7083-4-17 by Arunima Kohli, Marco A. Garcia, Rachel L. Miller, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13578755

ME/CFS as a Mitochondrial Disease Prohealth (26 April 2006) by David S. Bell, MD. http://www.prohealth.com/library/showarticle.cfm?libid=13611

 Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders. Nutrition reviews, Vol. 71, No. 6. (June 2013), pp. 353-369, doi:10.1111/nure.12024 by Philip B. Busbee, Michael Rouse, Mitzi Nagarkatti, Prakash S. Nagarkatti. http://www.citeulike.org/user/kimberlykramer2015/article/13407541

Toward understanding the role of aryl hydrocarbon receptor in the immune system: current progress and future trends. BioMed research international, Vol. 2014 (2014) by Hamza Hanieh. http://www.citeulike.org/user/kimberlykramer2015/article/13579639

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

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

Reprint Jan 7,2010

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
Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., Oukka, M., and Weiner, H. L. (2008). Control of treg and th17 cell differentiation by the aryl hydrocarbon receptor. Nature, 453(7191):65-71. http://www.citeulike.org/group/5070/article/2578286