4 ms·

This group presented an abstract at ACR in the fall prior so it's nice to see it published now. https://acrabstracts.org/abstract/cxcl13-t-cell-differentiation-

by zeagle 2y ago

This group presented an abstract at ACR in the fall prior so it's nice to see it published now. https://acrabstracts.org/abstract/cxcl13-t-cell-differentiation-in-systemic-lupus-erythematosus-is-controlled-by-opposing-effects-of-aryl-hydrocarbon-receptor-and-type-i-interferon/ https://acrabstracts.org/abstract/cxcl13-t-cell-differentiat... if you don't have journal access to the Nature article. Kudos to them for landing a nature publication but I really would temper this level of excitement (??a top link on HN??) at a basic science research publication discussed in a press release from a university highlighting it's researchers. My read is it is down to decreased CXCL13 expression and type I interferon expression in blood of a small number of patients, controls, and cell culture which gives direction for further study. CXCL13 was published as a possible RA biomarker half a decade ago and crickets since then clinically. Is it causal or a consequence of chronic inflammation? Type I interferon signature has been looked at heavily for over a decade and is clearly relevant in SLE but still only just over about half of lupus patients have it and the signature is by definition broad expression of hundreds of genes that affect innate and adaptive immune system components. We DO need better treatments for lupus patients but it's a very variable disease in severity, clinically, and in terms of biomarkers making it difficult. I mean the best drug that everyone with lupus should be on barring a good reason is an old antimalarial (that doesn't treat COVID) and then we add to it. If you are interested in other new-ish therapies for lupus take a look at anifrolumab, belimumab, voclosporin, and even newer CAR T stuff. Important to consider the manifestations being treated with those in the studies e.g. belimumab with skin, joint, kidney but nothing for hematologic/cardiac/neurologic manifestations.

Kalanos 2y ago
I don't have much context, but the identification of the AHR receptor for the CXCL seems like the exciting part. From what I understand, it is easy enough to design an antibody once you know the right receptor to target
fasa99 2y ago
Exactly. When our car doesn't run well, a car with perhaps 20,000 parts, we take it to the mechanic who says "yup, issue was your spark plug, fixed". And even then, of course, the car issue may have been multifactorial. Maybe the spark plug failed because the fuel/air mix was off, for example, the spark plug was the symptom. But then we leap from the car with 20,000 parts to a body with a trillion cells each cell with a trillion molecules. The calculus of the fuel/air mix and the spark plug has now been blown out of proportion, as challenging as conceiving a 20 dimensional manifold or the size of the universe. And so my reservation with a paper like this, and in general, is people say, "yup, sure was the spark plug" and then get accolades and a Nature paper, when the core issue was the air fuel mix, the air fuel mix that is, times a trillion cells, times a trillion molecules. And I can't blame the authors. No shame in shooting for Nature and succeeding. No shame in these simplistic models, each one takes us a step further. But somewhere along the lines we're going to have think about the R&D of the big picture in non-hand-wavey ways.
- _Adam 2y ago
  > But somewhere along the lines we're going to have think about the R&D of the big picture in non-hand-wavey ways. How?
  - aftbit 2y ago
    Superintelligence
    - pixl97 2y ago
      Probably not a great solution.... When dealing with code we say refactor and simplify. Superintelligence my (rightfully) consider us too complicated and a 'big ball of mud' and replace us with version 2.0.
      - babyshake 2y ago
        Alignment? I suppose the type of alignment needed for superintelligence is to plead with it for mercy, on some level.
  - nanomonkey 2y ago
    Likely nanotechnology. Sensors that can reside in your body and give up to the moment details, and chemical factories that we can programmatically make adjustments to the body's existing pathways (reprogramming the immune system, etc.). In other words, better integration and faster feedback loops.
    - pixl97 2y ago
      Just wait till some small percentage people have random immune responses to the nanotechnology just creating another feedback loop in the system.
    - newzisforsukas 2y ago
      seems like dying is easier
w10-1 2y ago
Yes, pathways are complex and adaptive, but as I read the abstract (thank you!), they're suggesting a treatment path. The potential treatment is that the protein JUN can block IFN's increasing CXCL13 pathologically. It's testable in that JUN itself can be produced and delivered during acute phases to reduce flares, and could itself be a therapy. More lasting gene diagnostics and therapies may come from checking for dysregulated genes in the pathway and injecting genes to produce JUN. It's not promising, though, to the extent JUN wouldn't address an underlying IFN dysregulation.

by zeagle 2y ago

Kalanos 2y ago

I don't have much context, but the identification of the AHR receptor for the CXCL seems like the exciting part. From what I understand, it is easy enough to design an antibody once you know the right receptor to target

fasa99 2y ago

Exactly. When our car doesn't run well, a car with perhaps 20,000 parts, we take it to the mechanic who says "yup, issue was your spark plug, fixed". And even then, of course, the car issue may have been multifactorial. Maybe the spark plug failed because the fuel/air mix was off, for example, the spark plug was the symptom. But then we leap from the car with 20,000 parts to a body with a trillion cells each cell with a trillion molecules. The calculus of the fuel/air mix and the spark plug has now been blown out of proportion, as challenging as conceiving a 20 dimensional manifold or the size of the universe. And so my reservation with a paper like this, and in general, is people say, "yup, sure was the spark plug" and then get accolades and a Nature paper, when the core issue was the air fuel mix, the air fuel mix that is, times a trillion cells, times a trillion molecules. And I can't blame the authors. No shame in shooting for Nature and succeeding. No shame in these simplistic models, each one takes us a step further. But somewhere along the lines we're going to have think about the R&D of the big picture in non-hand-wavey ways.

_Adam 2y ago
> But somewhere along the lines we're going to have think about the R&D of the big picture in non-hand-wavey ways. How?
- aftbit 2y ago
  Superintelligence
  - pixl97 2y ago
    Probably not a great solution.... When dealing with code we say refactor and simplify. Superintelligence my (rightfully) consider us too complicated and a 'big ball of mud' and replace us with version 2.0.
    - babyshake 2y ago
      Alignment? I suppose the type of alignment needed for superintelligence is to plead with it for mercy, on some level.
- nanomonkey 2y ago
  Likely nanotechnology. Sensors that can reside in your body and give up to the moment details, and chemical factories that we can programmatically make adjustments to the body's existing pathways (reprogramming the immune system, etc.). In other words, better integration and faster feedback loops.
  - pixl97 2y ago
    Just wait till some small percentage people have random immune responses to the nanotechnology just creating another feedback loop in the system.
  - newzisforsukas 2y ago
    seems like dying is easier

w10-1 2y ago

Yes, pathways are complex and adaptive, but as I read the abstract (thank you!), they're suggesting a treatment path. The potential treatment is that the protein JUN can block IFN's increasing CXCL13 pathologically. It's testable in that JUN itself can be produced and delivered during acute phases to reduce flares, and could itself be a therapy. More lasting gene diagnostics and therapies may come from checking for dysregulated genes in the pathway and injecting genes to produce JUN. It's not promising, though, to the extent JUN wouldn't address an underlying IFN dysregulation.