6 ms·

Autoimmune diseases, of which lupus is but one of many, are essentially black boxes. It’s proven extraordinarily difficult to develop therapies in this area. As

Autoimmune diseases, of which lupus is but one of many, are essentially black boxes. It’s proven extraordinarily difficult to develop therapies in this area. As such, this is great news. Hopefully this research will encourage pharmaceutical and biotech companies to invest more resources into translating research findings into effective therapies. 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.

atombender 2y ago
The aryl hydrocarbon receptor (AhR), which is key to this discovery, appears to be super relevant to psoriasis, another autoimmune disease. 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-discovery-chronic-inflammation/ https://newsroom.uvahealth.com/2023/02/15/multiple-sclerosis...
- BenFranklin100 2y ago
  Great comment, thanks. I’m looking forward to reading the paper.
- A_D_E_P_T 2y ago
  Good post. One small correction: Tapinarof isn't an AhR inhibitor, it's an AhR activator, an agonist. 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.
  - atombender 2y ago
    Ah, thanks. I assumed tapinarof was an inhibitor, as the papers on its mechanism describe it as downregulating cytokines. It appears the exact mechanism isn't quite clear. Bissonette et al 2021 [1]: 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. It looks like tapinarof modulates the signaling behaviour of AhR, but so far the precise mechanisms are educated guesses. 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%2932906-6 https://www.jaad.org/action/showPdf?pii=S0190-9622%2820%2932...
    - A_D_E_P_T 2y ago
      This open-access paper is pretty interesting with respect to mechanisms of action and how tapinarof differs from other stilbenes and AhR agonists: https://www.jidonline.org/article/S0022-202X(17)31543-9/fulltext https://www.jidonline.org/article/S0022-202X(17)31543-9/full... 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...
kylehotchkiss 2y ago
I have a good feeling we're going to make a fairly big impact on cancer in our lifetimes with mRNA and other new discoveries in our lifetime. Autoimmune issues I'm feeling much less confident about. It seems like so many of the therapies are "turn down the immune system". I wish there was wider study into autoimmune derived mental health complications too. Maybe I'm totally wrong on this (and I'm very OK to be proven wrong) but maybe there's something to find here.
- roywiggins 2y ago
  There is evidence that inflammation is among the causes of depression: https://wapo.st/3xHLze1 https://wapo.st/3xHLze1 > 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.
  - Aerroon 2y ago
    Is this why something like vitamin C can help with depression?
    - theGnuMe 2y ago
      What the mechanism?
      - sharpshadow 2y ago
        „Vitamin C supplementation attenuates the oxidative stress (lipid peroxidation) and inflammatory response (IL-6) to a single bout of exercise.“[1] 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. 1. https://pubmed.ncbi.nlm.nih.gov/32162041/ https://pubmed.ncbi.nlm.nih.gov/32162041/
fnord77 2y ago
> Autoimmune diseases, of which lupus is but one of many, are essentially black boxes. 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.
_glass 2y ago
Yes, for Hashimoto's thyroiditis there seem to be some approaches: https://pubmed.ncbi.nlm.nih.gov/38621508/ https://pubmed.ncbi.nlm.nih.gov/38621508/ Let's see how this plays out.

atombender 2y ago

The aryl hydrocarbon receptor (AhR), which is key to this discovery, appears to be super relevant to psoriasis, another autoimmune disease. 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-discovery-chronic-inflammation/ https://newsroom.uvahealth.com/2023/02/15/multiple-sclerosis...

BenFranklin100 2y ago
Great comment, thanks. I’m looking forward to reading the paper.
A_D_E_P_T 2y ago
Good post. One small correction: Tapinarof isn't an AhR inhibitor, it's an AhR activator, an agonist. 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.
- atombender 2y ago
  Ah, thanks. I assumed tapinarof was an inhibitor, as the papers on its mechanism describe it as downregulating cytokines. It appears the exact mechanism isn't quite clear. Bissonette et al 2021 [1]: 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. It looks like tapinarof modulates the signaling behaviour of AhR, but so far the precise mechanisms are educated guesses. 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%2932906-6 https://www.jaad.org/action/showPdf?pii=S0190-9622%2820%2932...
  - A_D_E_P_T 2y ago
    This open-access paper is pretty interesting with respect to mechanisms of action and how tapinarof differs from other stilbenes and AhR agonists: https://www.jidonline.org/article/S0022-202X(17)31543-9/fulltext https://www.jidonline.org/article/S0022-202X(17)31543-9/full... 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...

kylehotchkiss 2y ago

I have a good feeling we're going to make a fairly big impact on cancer in our lifetimes with mRNA and other new discoveries in our lifetime. Autoimmune issues I'm feeling much less confident about. It seems like so many of the therapies are "turn down the immune system". I wish there was wider study into autoimmune derived mental health complications too. Maybe I'm totally wrong on this (and I'm very OK to be proven wrong) but maybe there's something to find here.

roywiggins 2y ago
There is evidence that inflammation is among the causes of depression: https://wapo.st/3xHLze1 https://wapo.st/3xHLze1 > 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.
- Aerroon 2y ago
  Is this why something like vitamin C can help with depression?
  - theGnuMe 2y ago
    What the mechanism?
    - sharpshadow 2y ago
      „Vitamin C supplementation attenuates the oxidative stress (lipid peroxidation) and inflammatory response (IL-6) to a single bout of exercise.“[1] 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. 1. https://pubmed.ncbi.nlm.nih.gov/32162041/ https://pubmed.ncbi.nlm.nih.gov/32162041/

fnord77 2y ago

> Autoimmune diseases, of which lupus is but one of many, are essentially black boxes. 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.

_glass 2y ago

Yes, for Hashimoto's thyroiditis there seem to be some approaches: https://pubmed.ncbi.nlm.nih.gov/38621508/ https://pubmed.ncbi.nlm.nih.gov/38621508/ Let's see how this plays out.