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JAK/STAT pathway and hair loss

Changexpert

Senior Member
Messages
112
Along with CFS, I have been suffering from hair loss for a while at a such young age, so hair loss research has been one of my primary focus lately. The idea of inhibiting JAK pathway stems from a theory that hair loss is caused by autoimmune response creating unnecessary inflammation.This experimental success for hair regrowth was an accidental finding, which was confirmed by a rat study recently. The first accidental finding was noticed with a rheumatoid arthritis patient, taking JAK inhibitor drug orally. However, researchers concluded that inhibiting JAK can create a new host of problems, so oral ingestion is not suitable for hair loss purpose. As a result, the rat experiment was done topically, not orally.

http://www.belgraviacentre.com/blog...s-drug-xeljanz-may-have-serious-side-effects/
http://www.nbcnews.com/health/health-news/cancer-drug-could-be-baldness-remedy-too-n450256

The difference among JAK1, 2, and 3 is really subtle, as all of them are involved in many pathways as shown in the diagram attached below.

A diagram that shows differecne among different JAK (1,2,3) pathways
http://www.ebioscien...tat-pathway.jpg

I think inhibiting JAK-2 is not as beneficial because it will result in HGH inhibition, but that's just my guess.

JAK1 - Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor

JAK2 - Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.

JAK 3 - Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.

Source: http://www.uniprot.org/uniprot/P52333


On the other hand, here is an interesting blog post about how STAT is involved in immune system mediation. The post focuses on CFS/ME instead of hair loss.

http://optimalprediction.com/wp/ori...e-immune-system/comment-page-1/#comment-81716

I personally think CFS and hair loss are closely related because I think both of them happen from immune system dysfunction, whether it be due to overstimulation, lack of suppression, deficiency, or too much suppression. Unfortunately, there has not been much study to back up such claim. Keep in mind that correlation is not equal to causation, and I am not saying one causes another.

The post discusses how CFS/ME patients (mainly ME) are more prone to infection due to decreased function of STAT1 that leads to Th2 dominance, resulting in decreased level of IL-22, IFN gamma, AND INCREASED LEVEL OF TGF-B. Many studies concluded that TGF-B is elevated in the scalp of hair loss patients. This theory seems very fitting, but its conclusion is the OPPOSITE of what researchers have been conducting (first two articles).

If dysfunctional STAT1 is the cause of increased TGF-B, it would not make much sense from TGF-B perspective to inhibit JAK pathway. Since JAK is a precursor of STAT pathway, JAK inhibition would decrease the available reactants for STAT1 process, which would ultimately increase TGF-B even more. From all this, we can see that there are at least two schools of thought.

1. Immune system deficiency (Th1) causes Th2 dominance, resulting in increased TGF-B, allowing infections to occur/proliferate more easily. (what the blog post suggests)
2. Immune system overdrive causes autoimmune response, which can be mediated by inhibiting JAK pathway (what the researchers are working on)

I can see both theories being plausible, but my experience agrees more with second theory. I have never tolerated any immune booster supplements like IP6, beta glucan, mushroom extracts (reishi, shiitake, maitake, chaga, cordyceps, etc), and even vitamin C; they always caused more body rashes, scalp bumps, and acne.Other therapeutic supplements like methyl B12 and iodine (kelp, Lugol's, nascent) always resulted in side effects mentioned above, along with insomnia and muscle cramps.

It's always tough when two great sounding theories are contradictory of each other. I would love to hear different opinions on this topic. Thank you so much!

@Hip @adreno @heapsreal
 
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