Making A Case for Tregs and LPS in Multiple Chemical Sensitivity~!

If there is injury and disruption of activities of olfactory neurons that has a connection to memory- can alteration of these proteins be a factor in MCS because of alteration of signals that exist between them?

Different studies have shown some interesting things about the sense of olfaction. It would be interesting to understand better how long-term toxic exposures alter the general patterns of operation of receptors in neurons and what circumstances make one more vulnerable. Zhang expressed that gap junctons modulate activity and sensitivity of olfactory neurons that have been shown to have receptors for one odorant whereas, cortical neurons get imputs from a number of different ones. (Buck) Kay writes that when the nose is first exposed to odor the molecules are absorbed into the olfactory receptor cells that line the mucous membranes at the back of the nostrils.  There are some 350 varieties of these receptor cells, each specialized to detect certain odor molecules which convert this information into nerve impulses and then transmit them to the brain’s two olfactory bulbs (one for each nostril), which sit just behind the nose. The olfactory bulbs then translates the impulses into information the brain can understand and are sent on to the olfactory cortex where the "odor information" is processed.

Several recent studies show disruptions in the sense of smell are indicative of the early signs of diseases including Alzheimer's disease, autism, Parkinson's disease and schizophrenia. Dr. Wilson, an expert in the neurobiology of olfaction explains that olfaction is a unique "sense" because it has direct links to the amygdala that is important for regulating emotion and physiology and to the prefrontal cortex that is involved with cognition and planning.  He also points out that this connection is also the short path that links olfaction with memory. (Kay) As noted, olfactory disfunction is a "early-warning" sign of schizophrenia and Turetsky's data indicates structural and functional abnormalities run from the cortex to the olfactory system. "These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression." This is also in line with some of the most current hypotheses of neuroinflammation and epigenetic influences in autism.

  "gap junctional communication in the olfactory epithelium modulates olfactory activity at the peripheral level and alters glomerular activation patterns (odor maps) in the olfactory bulb. Topological changes in odor maps due to gap junctional modulation could affect perception of odor quality or quantity." (Zhang)

To what extent do disruptions of Tregs contribute to disease development?

Many patients that have chemical sensitivity describe that the worst of the symptoms began occurring after a bout of infection. Multiple chemical sensitivity is a condition where symptoms such as nausea, respiratory problems, mood changes, cognitive problems and numerous other repored symptoms occur at a very low exposure of an "odor" stimulus. In the past, we have suggestedTreg impairment may be important for the development of many responses in MCS which may be long lasting or transient depending on factors including other secondary exposures that influence or prevent their activity. In addition, Treg disfunction has been implicated in a number of co-morbid health conditions such as inflammatory bowel disease and the sensitivities in autism. Interestingly, many common current treatments for MCS were used for treatments for autism before they were used for MCS.  Recent reports have also suggested that suppression of regulatory T cells from air pollution may be an important factor in the development and augmentation of respiratory disease like asthma. (Berkley) Air pollutants and particulate matter contain a variety of contaminants including LPS endotoxin from bacteria, hydrocarbons and metals. A recent study demonstrates that LPS a common contaminant of most environments can alter the expression of Cx43 and caveolin-3. The former Cx43 is a connexin protein that has been found to be important for the integrity of gap junctions shown to dictate olfactory sensitivity. Interestingly, regulatory T cells also play a role in the communication activities of gap junctions. Taking these recent studies into consideration the newest research on regulatory T cells in promotion of the adaptive response and maintaining tolerance support, one could propose that altered communication may play a role in chemical sensitivity and odor and olfactory function and prvode parallel support to the recent research of how Tregs disfunction may influence respiratory problems from air pollution. In addition, because their is a relationship gap functions to activity of NO/cGMP and its downstream targets and related biological roles in relation to memory -- this could explain some of the cognitive problems associated with MCS. Generally, suppression of Tregs and their role in gap function has implications for both animals and humans. In animals impairment of the olfactory system may negatively influence instinctual patterns of navigation and other behaviors.



Related: Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

****Read more research blogs: Kimberly Kramer
















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The Logic of Smell. MedGadget, Internet Journal of Emerging Medical Technologies. Retrieved on October 14, 2010. http://medgadget.com/archives/2005/05/
BMC Neuroscience, Vol. 11, No. 1. (2010), 108. http://www.citeulike.org/user/HEIRS/article/7724812?show_msg=already_posted
Yang, Sarah. Air pollution alters immune function, worsens asthma symptoms. UCBerkelyNews.com. Retrieved on 10/13/2010.  http://www.berkeley.edu/news/media/releases/2010/10/05_asthma.shtml
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González-Flores, O., Beyer, C., Lima-Hernández, F. J. J., Gómora-Arrati, P., Gómez-Camarillo, M. A., Hoffman, K., and Etgen, A. M. (2007). Facilitation of estrous behavior by vaginal cervical stimulation in female rats involves alpha1-adrenergic receptor activation of the nitric oxide pathway. Behavioural brain research, 176(2):237-243. http://www.citeulike.org/user/HEIRS/article/8006383
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Li, D.-q., Li, X.-j., Duan, J.-f., and Cai, W. (2010). Wuling capsule promotes hippocampal neurogenesis by improving expression of connexin 43 in rats exposed to chronic unpredictable mild stress. Journal of Chinese Integrative Medicine, 8(7). http://www.citeulike.org/user/HEIRS/article/7971605

Il-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats

"Orshal, J. M. and Khalil, R. A. (2004). Interleukin-6 impairs endothelium-dependent no-cgmp-mediated relaxation and enhances contraction in systemic vessels of pregnant rats. Am J Physiol Regul Integr Comp Physiol, 286(6):R1013-1023."


Read more: CiteULike: Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats:

Cell signaling mediated by nitrated cyclic guanine nucleotide.

"8-Nitro-cGMP activated the Nrf2 signaling pathway by triggering dissociation of Keap1, via S-guanylation of its highly nucleophilic cysteine sulfhydryls. We also determined that S-guanylation of Keap1 was involved in cytoprotective actions of NO and 8-nitro-cGMP by inducing oxidative stress response genes such as heme oxygenase-1"


Read more: CiteULike: Cell signaling mediated by nitrated cyclic guanine nucleotide.:

NO/cGMP and Nrf2 --- The First Study that Identifies a Relationship~!

The Critical Role of Nitric Oxide Signaling, via Protein S-Guanylation and Nitrated Cyclic GMP, in the Antioxidant Adaptive Response — JBC: "first substantial corroboration of the biological significance of cellular 8-nitro-cGMP formation and potential roles of 8-nitro-cGMP in the Nrf2-dependent antioxidant response."

NO/cGMP signaling pathway limits inflammatory degeneration of dopaminergic neurons: via regulation of HO-1

"NO-cyclic GMP signaling pathway promotes the induction of HO-1 specifically in dopaminergic neurons, which acts as an endogenous protective system to limit inflammatory degeneration of this cell population."

CiteULike: Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: cell type-specific regulation of heme oxygenase-1 expression.:

Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.

"These results suggest that, by recruiting cyclic GMP and PKG, nNOS-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons."

Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.:

Exposure to Different PCBs during Development Effect NO/cGMP Pathway Differently7~!

"These data are consistent with the following possible mechanisms: (1) developmental exposure to PCBs 138 or 180 reduces the amount of NMDA receptors in cerebellum, which would contribute to reduced function of the glutamate-NO-cGMP pathway, which, in turn, would be a main contributor to the impairment of the ability to learn the Y maze task. (2) Developmental exposure to PCB52 increases extracellular GABA in cerebellum, which would contribute to motor coordination impairment."


CiteULike: Developmental exposure to polychlorinated biphenyls 52, 138 or 180 affects differentially learning or motor coordination in adult rats. Mechanisms involved.:

Pathway Impairment that Regulates Stress Response Could Lead to A Variety of Environmental Diseases

A recent study determined that caffeine can be a preventative against some of the health effects in Parkinson's disease caused by pesticides. The following pathway is a good representation of the NO/cGMP pathway that is more than likely effected by caffeine in these conditions and can account for some of the locomoter problems in PD. As one can see, expression of other proteins including BDNF rely on its activity. In other blogs, we have noted that BDNF is altered in environmental illnesses including CFS and may account for mood changes that occur with the condition. Proper signaling of the NO/cGMP pathway is important for a number of health conditions because the pathways are consistently activated by a number of different xenobiotics and environmental cues.

Alterations in the functioning of Nrf2 and other conditions like excretory defects that increase ammonia levels with negatively impact this system. While NO is an important component of this pathway - the actual dysfunction is not related to peroxynitrite, although oxidative stress to some may increase dysfunction though loss of NO signalling. Madhusoodanan explains that in this case, "nitric oxide is a short lived free radical species synthesized by NOS. The physiological role of NO depends on its local concentration as wells as the availability of downstream targets. At low levels, activation of guanalyl cyclase is the major event by NO. The resulting elevation of cGMP serves as an regulator of many events." I suggest that many environmental diseases including CFS and MCS are probably due more to the impairments of NO/cGMP which is also negatively effected by endogenous gases including ammonia and the impairment of the system results in astrocyte damage. Because Nrf2 is also neuroprotective --- alterations in Nrf2 will contribute to neural injury. Also, cGMP inhibits the protein GSK-3b which is an off/on switch for Nrf2. Studies have demonstrated that Nrf2 regulates the antioxidant complexes of HO-1/CO which modulates CRF (which can be activated by odors) and CO activates cGMP. These pathways seem to strongly suggest that Nrf2 ultimately may influence the regulation of the stress response from environmental cues. In any case, HO-1/CO does modulate the CRF system which can be activated by response cytokines such as Il-1.

Recent studies show that increasing Nrf2 may be beneficial in limiting neural injury and in this case, I would say it probably would too. The article discusses hormetic responses that we have also discussed at length and as Mattson describes "recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors." This of course may act on activities involved in methylation.



Notes:

• Diabetes exacerbates functional deficiency of NO/cGMP in ED

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Yang, R., Wang, J., Chen, Y., Sun, Z., Wang, R., and Dai, Y. (2008). Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. J Androl, 29(5):586-591. http://www.citeulike.org/user/HEIRS/article/7170883
Nisoli, E. and Carruba, M. O. (2006). Nitric oxide and mitochondrial biogenesis. J Cell Sci, 119(14):2855-2862.http://www.citeulike.org/user/HEIRS/article/7170901