You guys hear me talk about different immune cells and how they drive inflammation and tissue destruction and autoimmunity. Let’s put those discussion thoughts together to explain things a bit more!

Epithelial (gut, lung, sinus) inflammation drives the epithelia to release TSLP, IL-33, and IL-25 (inflammatory immune cytokines). These drive naïve T cells toward Th2 polarization which means that Tcells that haven’t derived yet end up forming into Th2 cells causing Th2 dominance. These same cytokines also drive the polarization and proliferation of ILC2’s, which are part of the Th2 system. ILC2’s use IL-13 to activate MDSC’s. MDSC’s make an abundance of TGFβ. TGFβ drives the formation of reactive oxygen species (ROS). ROS deplete glutathione (GSH). Low glutathione is associated with a shift away from Th1 polarization toward Th2. This yields:

Epithelial inflammation  >  TSLP/IL-33/IL-25  >  Th2/ILC2  >  MDSC  >  TGFβ  >  ROS

>  Low GSH  >  loss of Th1  >  Th2 upregulation (loop)    and

> Low GSH  >  loss of barrier integrity  >  Leaky Gut  >  Worsening of Epithelial Inflammation (loop)

*The breakdown is put together by Dr. Yanuck*

A couple of clinically important points are worthy of attention:

Barrier integrity is supported by GSH (glutathione), so low GSH can also affect the blood brain barrier (BBB).

High TGFβ in many (though not all) situations is a reflection of Th2 dominance. If you have any symptoms of fibrosis, that is related to TGFb elevation.

GI dysregulation can play a particularly problematic role in the persistence of Th2 dominance, both from the point of view of instigation and persistence, and also from the point of view of GSH depletion worsening the failed barrier integrity in the gut and the BBB. (see the Clinical Pearls The Four Gut Brain Axes – Parts 1 & 2)

Because TSLP, IL-33, and IL-25 also directly drive mast cell numbers and degranulation, including the release of mast cell mitochondrial DNA fragments that inflame the epithelia, this loop connects with the self-driving mast cell degranulation loop.