AhR has been known for a long time, but it seems it's been somewhat mysterious until a series of recent breakthroughs. In 2022, an AhR inhibitor called tapinarof, sold as VTAMA, was launched, and has shown itself to be one of the most effective treatments for psoriasis to date. It's also unique in that it appears to have the ability to bring lasting remission. In the main clinical trial, patients who used VTAMA for one year and then stopped had a mean remission duration of 4 months until their psoriasis returned. That is unheard of for any topical medication used on psoriasis.
Blocking AhR has also shown promise in treating MS [1].
I haven't read the lupus paper, but often with papers like these, the "cause" turns out not to be the actual origin, but some cytokine or other protein that is more disease-specific than current drug targets. This lupus discovery appears to identify an imbalance that may be compensated for, but we still don't know what triggers the imbalance in the first place.
In some cases diseases turn out to be a genetic fault, but my money is on pathogens acting as the initial triggering event, which then spins the immune system into a vicious cycle of autoimmunity. In psoriasis we see this with strep bacteria, for example, but the exact mechanisms are not well understood. However, the mechanism that makes psoriasis chronic has been identified, a type of T-cell called a tissue-resident memory (TRM) T-cell. This type of cell acts as a kind of biological memory for infections.
[1] https://newsroom.uvahealth.com/2023/02/15/multiple-sclerosis...
Interestingly, tapinarof is a natural product -- a sort of bacterially-modified stilbene, a chemical cousin of resveratrol and pterostilbene -- and several other natural products also activate AhR. (Though perhaps not exactly in the same way.) The most potent and readily available of these is probably 3,3'-diindolylmethane.
Tapinarof was found to bind directly to AhR, resulting in
downregulation of inflammatory cytokines, regulation of
skin barrier protein expression, and antioxidant activity
... In a T-cell polarization assay, tapinarof markedly
inhibited T-cell expansion and Th17-cell differentiation
and reduced the production of IL-17, while also reducing
IL-17A and IL17F levels in a CD4 T-cell assay.
The story of tapinarof's discovery is fascinating. It's produced by a bioluminescent (!) bacillus P. luminescens that (quoting from the paper) "lives symbiotically within parasitic, soil-living entomopathogenic nematodes." It was observed in the 1950s that "the nematode did not putrefy once dead, in contrast to the rapid decay seen in the absence of the nematode," leading to the idea that the bacillus' metabolites had antimicrobial activity — which turned out to include what is now synthesized as tapinarof.
Coal tar is another semi-natural substance that is thought to act on AhR.
[1] https://www.jaad.org/action/showPdf?pii=S0190-9622%2820%2932...
And, yeah, good point re coal tar. AhR was once thought to be a toxin or junk receptor that activated liver enzymes for clearance of environmental waste and other chemical byproducts. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were, at one time, thought to be very similar. That might still be the case with respect to PXR and CAR, but I'm thinking that the way to bet is that there's more to them than was once thought...
https://onlinelibrary.wiley.com/doi/10.1155/2019/5847040
Also of note for those curious since I haven’t seen it mentioned yet, Dioxins are potent agonists of AhR.
My own interest in AhR is that it seems to play a role in metabolism. Lower levels of exposure to AhR activators seems to kick off a complicated series of effects that seem to ultimately lower metabolism, potentially being a factor in obesity. Higher levels of exposure to dioxins however results in wasting. AhR is poster child for hideously complicated biochemical relationships, so do be careful of simple summaries of exposure/response relationships.
I would be cautious of AhR agonists though, I recall coming across a number of potential negative associations in regards to cardiovascular health.
I'm a PhD student working on a new lupus diagnostic blood test approach [1]. Hoping to steer the project towards true clinical needs.
I'd love to ask for your feedback as a technologist + rheumatologist on a few lupus + RA diagnostic directions we're considering. Would they actually be useful in your practice?
Would you be open to a quick chat? My email is [email protected].
Many thanks!
[1] https://www.biorxiv.org/content/10.1101/2022.04.26.489314v5
It may be that VTAMA reduces TRM cells in the skin, which are the T-cells responsible for relapse. There's is an ongoing clinical trial right now called KNOCKOUT [1] that gives patients a "megadose" of Skyrizi, an IL-23 inhibitor that has, like VTAMA, been shown to reduce TRM cells. The idea is that a single huge dose could effectively cure psoriasis, or at least suppress it for a very long time. The results so far show that 83% of patients achieved complete clearance after six months, which was sustained throughout the trial period. I'm confident it will be a game changer. Here [2] is an interview with the main researcher.
Among new psoriasis drugs, there is also Zoryve, a PDE4 inhibitor (same mechanism as Otezla) as a cream or foam, which has a different mechanism of action.
[1] https://www.hcplive.com/view/risankizumab-dose-clears-psoria...
[2] https://www.hcplive.com/view/rizankizumab-knockout-study-and...
The immune system has many branches, and you can effectively deplete one branch of the immune system while preserving the other branches to fight infection. For example with MS a very effective treatment is CD20+ B cell suppression, as rituximab does. For many people diagnosed with MS this has been effectively a "cure," in the sense that while they need to continually deplete their CD20+ B cells, their disease doesn't progress in any meaningful way, and their immune systems remain largely able to fight infection.
So we don't need to wholesale "turn down" the entire immune system for many autoimmune diseases. Rather, we need to surgically target specific parts of it and either suppress those parts or modify their behavior. Given the success we've seen with ritixumab and MS I'm more optimistic about our prospects for finding effective treatments for autoimmune conditions.
No, the immune system is not controlled by our microbiome. The microbiome interacts with, and modulates the immune system in various ways, but it's hardly "controlling" it. There are germ-free animal models with sterile guts, which demonstrate that you can live without a microbiome - of course not 100% healthy, but they can still live and reproduce.
The immune system is modulated by a lot of things: circadian rhythm, environmental stress, nutrients, etc. Yes, the gut microbiome is one of them. But let's be a bit more nuanced than Joe Rogan or The Liver King.
> pro-inflammatory drugs can induce people to become depressed, which suggests a causative link. In one seminal study published in the New England Journal of Medicine, Miller and his colleagues conducted a double-blind study of 40 cancer patients undergoing treatment with interferon-alpha, an inflammatory cytokine.
> Though none of the patients had depression to begin with, the inflammatory agent had a striking effect: Many became depressed, a finding that has been consistently replicated.
Vitamin C is essential and gets consumed by the body and needs to be replenished. For example during sickness the Vitamin C consumption is higher which could lead quickly to low levels.
There is evidence that things that reduce systemic inflammation help with depression. Fish oil, or more generally a balanced omega-3/omega-6 intake is one example. Curcumin is another. However the effects are modest, which is probably to be expected with a condition as diverse as depression.
Recently (and still in many cases) "turn down the immune system" was the treatment for most cancers. Of course, the purpose of anti-cancer drugs isn't to turn down the immune system. It just happens that the side effect of drugs that target cancer cells also target other rapidly-dividing cells like hair, endothelial, and immune cells.
In fact, chemotherapy drugs like Methotrexate are prescribed - at lower doses than for cancer patients - to people with Lupus and other autoimmune diseases.
There are similar challenges with cancer and autoimmune diseases, so progress in one might help progress in the other.
From the article: "They are now working to find ways to deliver these molecules safely and effectively to people." This is a challenge for many potentially effective cancer treatments as well.
Just as antivirals are actually ‘stop cell division’
Neither of which inspire any confidence
Hardly. Treatments are down to the kinase level these days, which is just one step away from the gene transcription factors.
In fact it is pretty amazing how well understood the complex mechanism of autoimmune diseases are.
I haven’t read the paper yet, so I can’t comment on how this discovery might generalize to other autoimmune diseases, but one interesting bit about autoimmune diseases is that they tend to run in packs. This is suggestive there may be underlying mechanisms that are shared across autoimmune diseases.