Scientists discover a cause of lupus, possible way to reverse it

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.

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...

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.

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

I've had some sort of autoimmune thing hitting me almost every decade of my life (and then clearing up): eczema, asthma, vitiligo and most recently psoriasis. Usually quite mild, but I worry that the next one in the progression will be arthritis. Most doctors' explanations can be summarised into a shrug. Would be a relief to know what's going on in there.

I wonder if allergies can eventually be fixed somehow as well. There has to be an immune or autoimmune reason why some people have tons of allergies and other people are perfectly fine.

There is a study that claims that genes associated with autoimmune diseases increased survival during the black death epidemic by 40% and frequency of these genes increased a lot in the 14th century Europe [1]. I haven't yet seen independent confirmations but I can imagine that paranoid immune system can be beneficial depending on circumstances. If we eradicate autoimmune diseases then there's a chance we won't survive the next big pandemic.

[1] https://www.nih.gov/news-events/nih-research-matters/how-bla...

Agreed. I sure would love to eat gluten.

It has been my hope that the number of me/cfs cases would finally drive enough research into autoimmune disorders in general, that we might finally figure it out. It seems very poorly understood from an outside perspective.

I've encountered an individual who had fibro, me/cfs, pots diagnosis. Turns out his small nerve fibers were fried by an antibiotic. His skin punch biopsy showed reduced fibers. This may not be the case in everyone, but SFN is extremely under diagnosed.

He was a chemist, and he ended up healing all his symptoms with pirenzepine. If I recall correctly they did the skin punch biopsy again and his physician was stunned when they saw regrowth of the fibers.

Today, WinSanTor is in stage 3 trials with their drug. They designed a cream with main ingredient being pirenzepine. They are targeting diabetes but the med appears to work for small nerve fibers as well.

Small nerve fibers control so much that any time people have weird unexplained symptoms it should be explored.

Isn't thiamine tissue deficiency at the bottom of dysautonomia? Potentially leading to Alzheimer, MS, ALS over long periods of time if untreated depending on one's genetics and the way their body tries to adapt to it? I understand nobody tracks this over 30 years though. I think it's low-risk to try to address long-term tissue B1/B2/B3 deficiencies first and see if it helps.

"The initial symptoms of thiamine deficiency beriberi are those of dysautonomia [1], a broad term that describes any disease or malfunction of the autonomic nervous system. This includes postural orthostatic tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), vasovagal syncope, mitral valve prolapse dysautonomia, pure autonomic failure, neurocardiogenic syncope (NCS), neurally mediated hypotension (NMH), autonomic instability and a number of lesser-known disorders such as cerebral salt-wasting syndrome. Dysautonomia is associated with Lyme disease, primary biliary cirrhosis, multiple system atrophy (Shy–Drager syndrome) Ehlers–Danlos syndrome and Marfan syndrome for reasons that are not fully understood [2]. It has been hypothesized that the association of dysautonomia with so many different diagnoses is because a common form of dysautonomia originates from high calorie malnutrition. This leads to loss of oxidative efficiency (pseudo hypoxia) and subsequent disorganization of ANS controls that are mediated through the limbic system and brainstem."

Very likely. All of these illnesses are diseases of the cells. We're entering the golden age of immune cell science. You figure out what immune cells are causing disease and how to restore them.

Here the T cells are imbalanced and a specific protein is found to regulate the imbalance but the interferon is countering the protein's effects. Now you can target that in many ways and run all sorts of clinical trials.

Maybe but the immune dysfunction goes further in ME/CFS its not just a problem of reduced CD4 and heightened CD8 (which are the two cell types they seem to be talking about) its a wider set of oddities that seem related to exhausted cells with not enough energy stuck in "there is infection near by" operation mode. It might help reduce symptoms that are caused by the imbalance so it would certainly be worth a trial when they work out the details.

I have crohn's disease which is also autoimmune and directly related to ingesting certain things. I think a lot of autoimmunity has to do with intestinal bacteria and their relationship to our innate immune system. And to a lesser extent it seems that almost every aspect of life is effected by what we eat, how we feel, how we act, how we grow and die. Maybe in 100 years we'll have fecal tests and bacteria pills to catch and prevent a paradigm shifting amount of ailments.

I know I've tried tons of different diets and exclusions and things. I've got a pretty good list in my head of what i can and can't eat but it seems to change q bit every couple years. I used to not tolerate bread but eat sugar and it seems to have switched some time in the last decade. Anyways, i wish you luck with your journey and I'm glad you've found something that works for you

What do you eat for protein in the current diet?

What was your experience with fish?

I'm curious if you've looked into N-Glycolylneuraminic acid and whether that could be the issue? Does chicken cause an issue for you?

I'm sorry to hear about your Lupus diagnosis, and glad it's in remission. My doctor wanted to diagnose me with Lupus due to the facial rash and arthritis/joint pain, but I came back negative in all the bloodwork, which I think means about 98% sure don't have it. I found that I can treat the joint pain effectively with SSRIs (Fluoxetine, 20 mg is enough to wipe it out after a few weeks). My mother has MCAS and my sister and aunt have UC, so I feel like I'm tripping through a minefield trying to navigate whatever autoimmune issue this is....and I have a PhD in biochemistry.

In the vegan community there is lost of discussion of animal products causing auto immune issues. A compromised gut lining will let intact animal proteins into the body. The immune sees the animal foreigners but also attacks our body; us being animals too.

Type 1 diabetes, aka childhood diabetes, is thought to be from casein in A1 milk; where the immune system attacks the beta cells of the pancreas. Seems plausible to me; rates of dairy consumption seem to correlate with type 1. (see Finland).

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.

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.

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

If these toxins build up in animal cells - why would you eating meat (that must then have a much higher concentration) not expose you to the same toxins?

This idea that plants are toxic and meat is healthy is absurd in the extreme. Historical evidence shows humans at mostly a plant based diet for most of our evolution. And the various large and strong herbivores are completely contradictory to your thesis. It's similar to flat-earth in how easy it is to debunk.

Wouldn't then the cure just be to eat organic food, rather than meat of animals that were fed way worse crap than the average person? The whole premise makes no sense...

For me, it was the opposite. Cutting out meat and eating a lot of organic greens helped calm my immune system and reduce inflammation. In my experience, meat increased my inflammation, while greens decreased it. I think everyone is different, and it's not hard to test on yourself if you have noticeable symptoms like joint pain, as I did.

Maybe if one more painfully unfunny person repeats this tired joke that we see every time lupus is mentioned, it'll finally be funny. Let's find out!

but it was never lupus anyway. mostly.

I don't even need to read the article, the answer is more mouse bites

Time to bring it back for an special episode where House say's it's not lupus, but it turns out it is and they find out thanks to an intern, and then they cure it using this new therapy.

To be fair, House's plots usually reiterated, "It's never Lupus."

(And the one time it actually was had a rather disappointing reveal, IMO)

Both reactions make sense to me. Too much AHR activation suppresses immune response leading to cancer proliferation due immune cells not culling cancerous cells, but too little leads to auto-immune conditions. It's definitely like a large sloppy code base with lots of implicit overlaps and global effects.

Smoking is supposed to be a risk factor so who knows.

There's definitely a genetic component but it would be interesting if those environmental factors impacted prevalence or severity.

Autoimmune disorders in general might be worse/more common in countries where kids grow up in clean environments. There's already some discussion on this with regard to allergies that I think has some credibility.

That’s wild, if true.

"You stash your drugs in a lupus textbook?" "It's never lupus"

Do you have research that shows that? What I've read is that there was no real evidence of that.

Came here for the House comment. Amazing how that show owned this word

Sometimes it is, a dear friend of mine is suffering from it. It's a really bad illness.

try LibSTC

It's not lupus!