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 Foxp
3-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."
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