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!
- mulptiple sclerosis
- diabetes
- arthritis
- uveitis
- lyme disease
- mercury-induced autoimmunity
- atopic dermatitis (initiation phase)
- inflammatory bowel disease
- bacterial infection
- mold infection
- lupus erythematosis
- lead-induced autoimmune disease
- allergy
- asthma
- chemical sensitivity
- parasitic infection
- atopic dermatitis (acute phase)
- inflammatory bowel disease
- bacterial infection
- malignancy
- mucosal immune abnormalities
- imbalanced gut flora
- intestinal barrier diysfunction
- systemic inflammation
- neuroinflammation
- neuroinvasion
- 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 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.
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
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