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.
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 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
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?
"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
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".
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
Anyway have a read and make a comment for the readers