Tregs and Environmental Illness!

In recent weeks, I have written a lot about Tregs and consider them to  be associated with environmental illness (Micovic).  I also have written how exposure to secondhand smoke and ambient air pollution combined lowers Tregs much more than individual exposures. (Kohli) Another study that drew my attention demonstrated that smoking causes a reduction in Tregs. According to the results of this study, the reduction of Tregs could last up to 24 months after cessation. (Qui) In addition, I also suggest that the Nrf2 and aberrant signaling of the AhR may also influence environmental diseases, including MCS.

"What are Tregs, more specifically Foxp3+ and what do they do?

Put simply, they are a type of lymphocyte that inhibit inflammation or suppress autoimmune responses. Tregs are believed to maintain a non-inflammatory environment in the gut and elsewhere, to suppress allergic immune responses to environmental and food antigens and to decrease chronic inflammation. Also, oral administration of antigens is meant to induce peripheral tolerance to subsequent exposures to them and oral tolerance is dependent on the expansion of the Treg population. This author explains that probiotic use in inflammatory bowel disease is followed by an increase in Tregs and a decrease in disease symptoms.
     One of the most important roles of Tregs is in the intestine where they maintain a balance of health and disease.  According to the author, "the maintenance of the balance between tolerance and immunity in the gut is governed by dendritic cells. They activate T cells in response to pathogens, but under normal conditions, these same cells promote non-inflammatory Tregs through the production of IL-10 and TGF-b. Further, experiments with probiotic use elicit a response on several levels. Others maintain that bacteria induces Fox3p+ development and production of immune cytokines. Several report that probiotic-induced tolerance originates via tolerogenic antigen-presenting cells (APC). The tolerogenic APCs contribute to generation of Tregs and regulation of inflammatory diseases. Incidentally, in mice lung models Fox3p+ Tregs produced from oral supplementation are more potent than mice without probiotic exposure and can prevent airway inflammation from allergies. Fox3p+ also seem to inhibit inflammatory protein pathways like NF-kb. Lastly, it is proposed that prevention of local inflammation by Tregs in the gut may modulate disease processes in distal organs. "(Workman)
          According to Issazadeh-Navikas, there is still a lot to learn about the immune balance and the status of Tregs. The most common Fox3p+ Treg is associated with immune regulation. generally, they can "suppress various kinds of cells including natural killer cells, dendritic cells, etc. They have an essential role in the hyperimmune response. (Navikas) Past studies show that Foxp3-expressing T cells appear shortly after birth and show that the development of autoimmune/inflammatory disease follows their depletion. (Sakagushi)

What Environmental Factors Increase or Decrease Tregs?

In a Nature article, the Ho and Steinman describe how Quintana et al cloned the homolog of Foxp3+ and like its human counterpart it is restricted to lymphocytes. You might remember how I stated that the Nrf2 and aberrant signaling of the AhR may contribute to environmental illnesses including MCS. In this article, the author claims "they have identified the AhR binding site in the Fox3p+ promoter near where other transcription factors have been found. Experiments with an AhR ligand TCDD shows that the AhR controls FOXp3+expression. Other experiments show that the FOXp3+ Treg can have increased levels of AhR and CP1A1. Resveratrol an AhR antagonist decreased CP1A1 and Foxp3+ expression but not the AhR expression."

Nouri reports there has been a shift in our view of autoimmune disease.   "It is characterized by tissue damage and loss of function due to an immune response that targets specific organs." (Visser)  In addition to genetics, making the individual react to "self" antigen, there is a loss of protective function of epithelial barriers that interact with the environment. There are several places where the epithelium interacts with the environment, they include the skin, the lungs, and the intestine. Recently, several models indicate increased intestinal permeability, often referred to as "leaky gut" plays a role in several diseases including inflammatory bowel disease, celiac disease and systemic autoimmune disease like type 1 diabetes.

Nouri goes on further to describe how a recently discovered protein called zonulin contributes to intestinal permeability. According to him, intestinal permeability leads to delivery of antigens that trigger muli-system responses leading to autoimmune disease. This begins by the antigens passing through barriers and tight junctions located between epithelial cells. He notes the exact mechanism is not clearly understood but the protein zonulin signals for the opening of the tight junction. Several diseases may be attributed to the dysfunction of tight junctions including environmental disease. In addition, inflammatory cytokines which are often elevated in inflammatory type disease like TNF-a and IFN-y have a regulatory effect on zonulin.

Contrary to what some studies say that changes in the intestinal barrier function and microbiota triggers autoimmune disorders. Nouri et al believes that increased intestinal permeability can be a cause of autoimmune reactions. In any case, Visser explains " a few preexisting conditions must be present for the development of autoimmune disease. The first is there is genetic susceptibility for the host system to recognize and misinterpret environmental antigens presented within the gastrointestinal tract. Second, the hose must be exposed to the antigen. Third, the antigen must be exposed to the gastrointestinal immune system passage from the lumen to the gut submucosa.  In all cases, increased permeability precedes disease and causes an abnormality in antigen delivery that triggers immune events, eventually leading to a multiorgan process and autoimmunity."
The role of Tregs in controlling gut inflammation has been known for a while now. What is important is that the depletion of them results in diseases like colitis. In addition, the loss of Tregs in the gut results in intestinal lesions. Also, it is suggested that "Tregs regulate intestinal inflammation induced by pathogenic bacteria. Foxp3+ Tregs regulate gastric inflammation and bacterial colonization and commensal-induced Tregs protect against pathogen-induced inflammation."

Issazadeh-Navikas et al. is one of the first to address how "dietary components affect Tregs in relation to inflammation and immune regulation. Because of this, the author points out that one must contemplate how dietary components affect the immune system and formation of tissue-induced Tregs and what it takes to produce them. The author cites one example of the Tregs produced in adipose tissue and their effect on insulin resistance. Unfortunately, not much is known about this.
As far as a high-fat diet, it reduces liver Tregs which are more susceptible to cell death from reactive oxygen species. It is not too far a stretch that dysregulation of ROS in other systems would lead to diseases in them from Treg loss. Tregs in adipose tissue effects insulin resistance related to obesity that accumulates with age. Tregs in obesity are decreased and also accompany inflammation. The function of Tregs in abdominal adipose tissue is still not understood, but it is assumed that oxidative stress contributes to the loss of Tregs resulting in increased inflammation and a change in the immune balance."

Kang et al has suggested that "both vitamin A and D are both inducers of Tregs. In one study, he explains that low vitamin D levels are found in autoimmune patients including rheumatoid arthritis and lupus. He notes that the increased generation of FoxP3+ was reported with both oral and topical vitamin D, but the mechanism is not known. He goes on to say that it is not known whether vitamin D induces Foxp3+ without the help of other molecules. As far as vitamin A is concerned, Kang found that vitamin A in high and low quantities elicits the production of different subtypes of Fox3p+. However, both subtypes, when transferred to mice with chronic intestinal inflammation, were able to reverse the inflammation."




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

[CD₄(+)Foxp3(+) regulatory T cells in inflammation and emphysema after smoking cessation in rats]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, Vol. 33, No. 9. (September 2010), pp. 688-692 by Shi-lin L. Qiu, Jing Bai, Xiao-ning N. Zhong, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13589256

Regulatory T Cells and Immune Tolerance The Cell, Vol. 133, No. 5. (30 May 2008), pp. 775-787 by Shimon Sakaguchi, Tomoyuki Yamaguchi, Takashi Nomura, Masahiro Ono. http://www.citeulike.org/user/kimberlykramer2015/article/13589889

The development and function of regulatory T cells. Cellular and molecular life sciences : CMLS, Vol. 66, No. 16. (August 2009), pp. 2603-2622, doi:10.1007/s00018-009-0026-2 by Creg J. Workman, Andrea L. Szymczak-Workman, Lauren W. Collison, Meenu R. Pillai, Dario A. Vignali. http://www.citeulike.org/user/kimberlykramer2015/article/4405817

Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Annals of the New York Academy of Sciences, Vol. 1165 (May 2009), pp. 195-205, doi:10.1111/j.1749-6632.2009.04037.x by Jeroen Visser, Jan Rozing, Anna Sapone, Karen Lammers, Alessio Fasano. http://www.citeulike.org/user/kimberlykramer2015/article/6208516

Intestinal Barrier Dysfunction Develops at the Onset of Experimental Autoimmune Encephalomyelitis, and Can Be Induced by Adoptive Transfer of Auto-Reactive T Cells PLos One (3 September 2014) by Mehrnaz Nouri, Anders Bredberg, Björn Weström, Shahram Lavasani. http://www.citeulike.org/user/kimberlykramer2015/article/13589022

The aryl hydrocarbon receptor: a regulator of Th17 and Treg cell development in disease Cell Research, Vol. 18 (2 June 2008), pp. 605-608 by Peggy P. Ho, Lawrence Steinman. http://www.citeulike.org/user/kimberlykramer2015/article/13589701

Influence of dietary components on regulatory T cells. Molecular medicine (Cambridge, Mass.), Vol. 18 (2012), pp. 95-110, doi:10.2119/molmed.2011.00311 by Shohreh Issazadeh-Navikas, Roman Teimer, Robert Bockermann. http://www.citeulike.org/user/kimberlykramer2015/article/13588993

High and low vitamin A therapies induce distinct FoxP3+ T-cell subsets and effectively control intestinal inflammation. Gastroenterology, Vol. 137, No. 4. (October 2009), doi:10.1053/j.gastro.2009.06.063 by Seung G. Kang, Chuanwu Wang, Satoshi Matsumoto, Chang H. Kim  http://www.citeulike.org/user/kimberlykramer2015/article/13591105

1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. Journal of immunology (Baltimore, Md. : 1950), Vol. 188, No. 11. (1 June 2012), pp. 5276-5282, doi:10.4049/jimmunol.1101211 by Seong Wook W. Kang, Sang Hyun H. Kim, Naeun Lee, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13591098

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

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