Sunday, 4 November 2018

More Salty stuff..

It has been suggested by "New England MS" that salt is a key problem in MS, Here they say this effect is mediated by β-catenin pathway.
Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DA. Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nat Immunol. 2018. doi: 10.1038/s41590-018-0236-6. [Epub ahead of print]

Foxp3+ regulatory T cells (Treg cells) are the central component of peripheral immune tolerance. Whereas a dysregulated Treg cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify an imbalance between the cytokines IFN-γ and IL-10 as a shared Treg signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human Treg subpopulations revealed β-catenin as a key regulator of IFN-γ and IL-10 expression. The activated β-catenin signature was enriched in human IFN-γ+ Treg cells, as confirmed in vivo with Treg-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-γ and IL-10 production under a high-salt environment, with skewed activation of the β-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-β-catenin loop in Treg cells linking environmental high-salt conditions to autoimmunity.

You asked about this paper.


Well what does this mean, I thought about read it, but don't have the time or the will to spend time to address this, as means little to your care.

 They did a lot of sexy science to support their hypothesis, including making mice that developed generalised autoimmunity.

They say "Whether a High Salt Diet directly affects MS clinical activity remains unknown" where they cite a reference that concludes "Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow‐up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20–29". Em?

Salt hypothesis has been discredited by a number of other researchers but the mechanisms are worth a Nature paper.

You can read what Wikipedia has to say about Beta catenin, the Wnt (pronounced Whint) pathway, on which beta catenin is supposed to be acting on, and the PTGER2,  through which the alterations of the cytokine balance is supposed to act, and please write in the comments on the importance you attach to this.

The study suggests a key role in both keeping Tregs functional and regulating the key pro- (Gamma interferon) and anti-inflammatory (interleukin 10) cytokines mentioned above. The study revealed that beta-catenin works together with a protein receptor called PTGER2 to trigger inflammation induced by a high salt intake. 

The authors conclude:"Our findings suggest that the beta-catenin-PTGER2 axis serves as a bridge between environmental factors and autoimmune disease by modulating Treg function, and this axis may be involved in the pathogenesis of autoimmune disease."

The clinical implications 

"Not only upregulation of [the] pro-inflammatory cytokine IFN-gamma but also downregulation of [the] anti-inflammatory cytokine IL-10 might mark dysfunctional [Tregs] in MS patients."
"Therefore, it would be ideal to work on [both directions]: prevent IFN-gamma and enhance IL-10, it's always important to balance pro- and anti-inflammatory arms together."


But where are we on this?


Prevent gamma interferon on mice and disease gets worse not better, but do it in humans 

Skurkovich S, Boiko A, Beliaeva I, Buglak A, Alekseeva T, Smirnova N, Kulakova O, Tchechonin V, Gurova O, Deomina T, Favorova OO, Skurkovic B, Gusev E.Randomized study of antibodies to IFN-gamma and TNF-alpha in secondary progressive multiple sclerosis. Mult Scler. 2001; 7:277-84.I

Patients who received antibodies to IFN-gamma showed statistically significant improvement compared to the placebo group--a significant increase in the number of patients without confirmed disability progression. This was supported by MRI data (a decrease in the number of active lesions) and systemic changes in cytokine status (a decrease in IL-1beta, TNF-alpha, and IFN-gamma concentrations in supernatants of actvated blood cells of these MS patients and an increase in TGF-beta production).

Seems to be correct

However enhance IL-10...I'm not so sure. Mention IL-10 to a T cell immunologist and they think immunoregulation. However it is a B cell growth factor too and so maybe not all good..

Wiki says for IL-10 :"It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production". 

"Contrary to expectations, rHuIL-10 treatment did not significantly impact disease in patients with Crohn's disease.or rheumatoid arthritis. rHuIL-10 treatment failed to achieve clinical significance in a randomized, double blind, placebo controlled Phase II trial in psorisis. Further investigation of rHuIL-10's effects in humans suggests that rather than inhibiting inflammation, rHuIL-10 is capable of exerting pro-inflammatory effects".

When we looked...

Croxford JL, Feldmann M, Chernajovsky Y, Baker D. Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J Immunol. 2001; 166:4124-30....the effect of delivering IL-10 was not straight forward and the  therapeutic was with a proviso, as you got more B cells and CD8 T cells in lesions.


tsF were immortalised fibroblasts that were transfected to make IL-10 (IL-10.tsF2). Tsf2 and Tsf4 were different cell lines


So the response to therapy can say a lot about the putative mechanisms on which they are based

In my opinion targeting cytokines is not a good approach, as cytokines exist in balances. Inhibit one and another goes up to compensate and vice versa. You say beta interferon and I say, yep point proven not the best approach.

Anyway have a read and make a comment for the readers

3 comments:

  1. "You say beta interferon and I say, yep point proven not the best approach."

    Do we even know how Beta Interferon works..?

    ReplyDelete
  2. Wiki says for IL-10 :"It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production"

    Wiki also says:

    IL-10 is linked to the myokines, as exercise provokes an increase in circulating levels of IL-1ra, IL-10, and sTNF-R, suggesting that physical exercise fosters an environment of anti-inflammatory cytokines


    Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals.[38] Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.[39] As a result, TNFα levels rise and result in inflammation.[40] TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.[40]

    One more reason for people with ppms to exercise

    :)

    Obrigado

    ReplyDelete
  3. Interestingly hi salt diet is linked to hypertension

    Via reduction of Beta hydroxybutyrate in the liver

    "As we searched through the literature we saw beta hydroxybutyrate has been observed increasing with exercise or calorie restriction. Both of those activities also reduce blood pressure. The key piece of our discovery is we now know that beta hydroxybutyrate decreases with salt consumption. This is a novel mechanism by which salt is tied to an increase in blood pressure," said Saroj Chakraborty, a fourth-year Ph.D. student in the UT Department of Physiology and Pharmacology and the paper's lead author.

    When that supplement reaches the liver, enzymes convert it to beta hydroxybutyrate. From there, it goes to the kidney where it was shown to reduce inflammation commonly associated with hypertension—and significantly decrease blood pressure in the process.

    "By fixing the kidney it is indirectly contributing to the lowering of blood pressure. There could be many other organs that it is impacting," Joe said. "We are studying the heart, blood vessels, brain and other organ systems. But this paper says that this molecule, predominately made in the liver, goes to the kidney, fixes kidney damage and controls your blood pressure."

    "There are certain patients who are not able to exercise for various reasons. This could prove to be a legitimate alternative for those individuals," Chakraborty said

    Great for lower mobility ppms

    :)

    https://medicalxpress.com/news/2018-10-required-team-hypertension-treatment-mimics.html

    Once again fasting and or exercise is key

    Obrigado

    ReplyDelete

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