New proof that narcolepsy is an autoimmune disease

[Andy]

Summary: Autoreactive cytotoxic CD8 T cells have been detected in people with narcolepsy type one. The finding suggests levels of the T-cell reactivity, combined with specific gene expression, may spur on the development of NT1.

Source: University of Copenhagen

Researchers from the University of Copenhagen have discovered autoreactive cells in persons suffering from narcolepsy. This is a new, important proof that the sleep disorder is an autoimmune disease. This knowledge may lead to better treatment of the chronic condition, the researchers behind the new discovery believe.

For many years, scientists have expected the sleep disorder narcolepsy of being an autoimmune disease, though without being able to prove it conclusively. Now researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen together with the Technical University of Denmark and Rigshospitalet have found a new, important proof that their presumptions were correct. The new research results have been published in the scientific journal Nature Communications.

https://neurosciencenews.com/narcolepsy-autoimmune-disease-10902/

 

[Hutan]

In most narcolepsy patients, the neurons that produce hypocretin and thus regulate our waking state have been destroyed.

Some interesting points:
They say that you usually need CD4 and CD8 T cells to work together to kill a cell.

To kill other cells, e.g. neurons producing hypocretin, CD4 and CD8 T cells usually have to work together. In 2018, scientists discovered autoreactive CD4 T cells in narcolepsy patients. This was really the first proof that narcolepsy is, in fact, an autoimmune disease. Now we have provided more, important proof: that CD8 T cells are autoreactive too,’

(Wikipedia is a less definitive, saying that CD4 T cells can help CD8 cells to work.)

Therefore, activation of CD4+ T cells can be beneficial to the action of CD8+ T cells

And they found autoreactive T cells in both healthy and narcoleptic people - but they seem to be assuming that the cells in healthy people haven't been activated.

In the study, the researchers studied and analyzed blood samples from 20 persons with narcolepsy. In addition, they analyzed blood samples from a control group of 52 healthy persons. In nearly all 20 narcolepsy patients the researchers found autoreactive CD8 T cells. But autoreactivity was not only found in persons suffering from the sleep disorder. The researchers also discovered autoreactive cells in a lot of the healthy individuals.

‘We also found autoreactive cells in some of the healthy individuals, but here the cells probably have not been activated. It is something we see more and more often with autoimmunity – that it lies dormant in all of us, but is not activated in everyone.

They suggest that a virus infection might activate the autoreactive cells in a genetically susceptible person.

Scientists still do not know what causes the disease. They expect a combination of genetics, autoreactive cells and a form of trigger to bring about the disease, e.g. a virus infection.

Activation of T cells seems to be a pretty complicated process - lots of possible things to go wrong. Some of the researchers at the Emerge conference seemed quite certain that ME isn't an autoimmune disease. I don't know how they can be sure.

 

[Jonathan Edwards]

And they found autoreactive T cells in both healthy and narcoleptic people - but they seem to be assuming that the cells in healthy people haven't been activated.

The problem with finding auto reactive T cells is that you can always find them if you cook your samples long enough. You can only draw conclusions if you find them in patients but not controls. The comment about seeing dormancy more and more often in autoimmunity also sounds to me like wishful thinking. More and more lab workers are finding things that probably don't mean very much but they don't have enough experience to realise that.

In the great majority of autoimmune diseases there is no evidence for any particular T cell auto reactivity. Narcolepsy looked as if it might be an exception but I am still to be convinced that the story is more than wishful thinking. The genetic link is with an MHC Class 2 type that binds to CD4 cells. I am not sure that we need CD8 cells involved.

 

[Alvin]

The fact Narcolepsy is autoimmune is news to nobody in the sleep research field, this has been known for over a decade, but assuming this is correct may explain a bit more about how the autoimmunity is killing the Orexin producing neurons

 

[Hutan]

The problem with finding auto reactive T cells is that you can always find them if you cook your samples long enough.

That's interesting - can you elaborate?

In the great majority of autoimmune diseases there is no evidence for any particular T cell auto reactivity.

My understanding is that Graves eye disease involves auto reactive T cells. It's what the specialist told me at the time and it's what papers seem to be saying e.g.

Recent findings have uncovered the importance of intercellular communication between autoreactive T cells and orbital fibroblasts. When orbital fibroblasts are activated, possibly by Graves' disease–related autoantibodies, they release T cell chemoattractants, initiating an interaction in which these cells activate each other. These interactions ultimately result in fibroblasts expressing extracellular matrix molecules, proliferating and differentiating into myofibroblasts or lipofibroblasts. Although the mechanisms underlying these processes are not completely understood, several currently available therapeutic strategies might interrupt the signaling between B and T cells and fibroblasts, thereby treating the clinical manifestations of TED.

I've had (apparently euthyroid) Graves eye disease, severely enough to have had a couple of operations to lower the lid on my left eye. And I rapidly lost most of the hearing in my left ear, finding the cause of which didn't seem of interest to the ENT specialist I saw. So, to me, in my ignorance, it doesn't seem impossible for auto reactive T cells to be attacking some other bit of my body to cause the symptoms I now have.

 

[Little Bluestem]

The last time I saw my doctor, she said that she thought my sleep problems were caused by narcolepsy. According to my sleep test, I do not have narcolepsy. However I did not sleep during the night part of the test. That may have caused problems with the day part (narcolepsy) test.

 

[Alvin]

The last time I saw my doctor, she said that she thought my sleep problems were caused by narcolepsy. According to my sleep test, I do not have narcolepsy. However I did not sleep during the night part of the test. That may have caused problems with the day part (narcolepsy) test.

The MWT is not as concrete as they think (assuming that was the day test). The night time test should have shown you smashing into REM sleep. Also cataplexy is a hallmark symptom.
In early narcolepsy the signals don't show as clearly, REM may not be obviously intrusive, cataplexy may not be apparent yet and the MWT is not accurate enough on its own to diagnose narcolepsy.

 

[Little Bluestem]

The sleep lab I was at had several rooms so that they could test several people at one time. They did warn us that one person was coming in late. They arrived just as I was dropping off to sleep. They made quite a bit of noise, which woke me up and I was not able to get back to sleep.

The day part of the test was supposed to detect narcolepsy. I wonder if it produced accurate results if the person had not slept the night before.

 

[Alvin]

The sleep lab I was at had several rooms so that they could test several people at one time. They did warn us that one person was coming in late. They arrived just as I was dropping off to sleep. They made quite a bit of noise, which woke me up and I was not able to get back to sleep.

I hate it when this happens. When i was really pushing on my body clock this was the bane of my existence (also had people living upstairs who must have had pet elephants). I currently have a neighbour who has a loud dog, i sometimes can use earplugs but sometimes still wrong timed barking and thats it for the night.

The day part of the test was supposed to detect narcolepsy. I wonder if it produced accurate results if the person had not slept the night before.

If its the try to fall asleep for 20 minutes 3 times then on its own it won't be enough on its own for many people. Some people can fall asleep whenever they want but don't have narcolepsy because they don't fall asleep against their will. For example many people with low thyroid will fall asleep on the day test, they just need levothyroxine

 

[Little Bluestem]

It's been long enough ago that I am not sure, but I think it was the try to fall asleep for 20 minutes 3 times thing. I did not fall asleep, so they said I did not have narcolepsy. I think they called it a sleep latency test.

 

[Alvin]

It's been long enough ago that I am not sure, but I think it was the try to fall asleep for 20 minutes 3 times thing. I did not fall asleep, so they said I did not have narcolepsy. I think they called it a sleep latency test.

Thats the multiple sleep latency test (MSLT), its not a perfect test but its one of the ones they use. When i did mine i had slept off my body clock for a 5 hour nap and was running on adrenaline and did not fall asleep any of the times. But i already knew i don't have narcolepsy so i just smiled and nodded.

Thats what i meant earlier when i said MWT which is a different test.

 

[Jonathan Edwards]

Me:The problem with finding auto reactive T cells is that you can always find them if you cook your samples long enough.

That's interesting - can you elaborate?

My understanding is that Graves eye disease involves auto reactive T cells. It's what the specialist told me at the time and it's what papers seem to be saying e.g.

This isa bittebchnical but I will try to elaborate. An auto reactive T cell isa T cell that will bind to a self antigen and activate in response. Similarly an autoantibody is an antibody that will bind to a self antigen and trigger a response in some effector cell.

For antibodies 'will bind' is fairly clearly defined as 'will bind with a dissociation constant of at least 10^-8'. That is to say that we know how much stickiness is effective binding and how much not for antibodies because they bind with a single non covalent interaction (to simplify things!). But for T cells how much stickiness is effective is dependent on a large number of other 'helping hand' molecules and internal cell factors.

And ultimately all antibodies have a tiny bit of stickiness for all antigens and all T cells have a tiny bit of sickness for all antigens. The difference is that for antibodies the difference between a meaningful stickiness to one antigen and weak stickiness to all the rest is fairly black and white. For T cells it is just a scale of grey. So if you cook T cells long enough in an assay and help them to stick all of them will stick and activate to any antigen (to simplify).

This is in part the reason why it took thirty years for people to get useful assays of T cell binding to antigens, whereas antibody assays had been done by students for decades. T cell assays are still almost too difficult to be any use for clinical work and as far as I know are only just about usable for TB responses, and TB is a pretty odd antigen anyway.

The Graves disease paper you quote shows how muddled people get about auto reactive T cells. What they are describing here is T cells responding to cytokines - which they will do even if they are not recognising an antigen. From the quote you give it does not looks if there is any reason to call these 'auto reactive' T cells. Immunologists have persisted in believing that autoimmune disease needs auto reactive T cells ever since T cells were found to direct B cell production of antibodies. But in general these autoeactive T cells have never been found - despite decades of trying. And there are alternative reasons why autoantibodies would be made WITHOUT auto reactive T cells. Realising that was what allowed us to develop rituximab for autoimmune disease.

 

[Hutan]

Very helpful, thanks for that detailed reply.