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

Effect of CRH on NO bioavailability, ROS production and antioxidant defense systems in endothelial EAhy926 cells.

The data indicate that CRH may act as a regulator of pro-inflammatory mechanisms inducing adaptation of endothelial cell function to local stress.

"Gougoura, S., Liakos, P., and Koukoulis, G. N. (2010). Effect of crh on no bioavailability, ros production and antioxidant defense systems in endothelial eahy926 cells. Free radical research, 44(7):803-812."
CiteULike: Effect of CRH on NO bioavailability, ROS production and antioxidant defense systems in endothelial EAhy926 cells.:

How odors activate the stress response and inflammatory mediators!

"enhanced IL-6 activity may stimulate the HPA axis at the level of the hypothalamus via a CRH-mediated mechanism For example, inhalation of citralva, a sample used during the study, may enhance the stress response or may itself act as a stress."


Effects of Odorants on the Hypothalamic-Pituitary-Adrenal Axis and Interleukin-6 (IL-6) and IL-6 Receptor mRNA Expression in Rat Hypothalamus after Restraint Stress -- Komori et al. 28 (9): 767 -- Chemical Senses: "enhanced IL-6 activity may stimulate the HPA axis at the level of the hypothalamus (Naitoh et al., 1988; Fukata et al., 1989; Navarra et al., 1991; Tominaga et al., 1991) via a CRH-mediated mechanism (Navarra et al., 1991; Lyson and McCann, 1992), i.e. inhalation of citralva may enhance the stress response or may itself act as a stress."

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