Multiple Sclerosis Causality

Multiple Sclerosis Causality

249 comments

·January 14, 2022

dm319

Here's a link to the article [0].

Just a bit of background - 95% of humans will experience infection with EBV at some point in their lives. Once you're infected, it remains latent, only flaring up in particular circumstances. MS is an autoimmune disease, like many others, and this paper does not imply that EBV directly causes MS. Obviously, as so many more people have EBV than have MS, EBV infection does not completely explain why people get MS.

Just to put a small caveat to the paper. The comparison is to EBV 'seronegative' population - this is a minority of people (i.e. people who do not have evidence of being infected with EBV). You could argue this is an 'unusual' population in the first place and there's something about them that provides protection from MS.

Another point is that EBV is a risk factor, there are other risk factors known too. I think the key to understanding a lot of autoimmune diseases is to understand how our adaptive immune system works. Our immune response is a very complex cell-to-cell interaction between millions of cells all with different roles, and how the immune system decides whether something is a threat or not is not, and how to respond to it, is not yet clear.

[0] https://www.science.org/doi/10.1126/science.abj8222

dekhn

At least part of the adaptive immune system is implemented in the thymus. As an infant, the thymus makes examples of nearly every type of cell in the body and uses it as negative labelled examples to tune the false positive detector so it doesn't identify self as threat. From an information theory perspective, that's pretty extraordinary (you don't normally expect differentiated cells in an organ to act like cells from another organ).

Another part of the adaptive immune system randomly shuffles different regions of genes together to produce enormous diversity (searching for a rare example of something that "works"), then picks the proteins from those genes that work best and distributes them throughout the body.

Pretty amazing stuff.

dm319

Yes, it's really fascinating stuff. Just to add to that, cells must present a continuous sample of their proteasome on the cell surface in the form of a short peptide 9-12 amino acids long. T cells will recognise when the cell is producing protein it shouldn't be (i.e. because it became cancerous or infected with a virus), even if only one amino acid is incorrect.

It learns this in the thymus, which has a bizarre gene called AIRE which switches on genes from all over the body, essentially creating a representation of the entire body in the thymus gland as a sort of sandbox before they are let out.

However, we don't have enough T cells to recognise every possible sequence of 11 amino acids (which would weigh around 1.5 tons), so T cells must be so-called 'cross-reactive'[1]. And therefore other factors must go into how T cells respond to abnormalities.

[1] https://www.nature.com/articles/nri3279

dekhn

yep, i was referring to AIRE without naming it. I saw a talk about it years ago and it blew my mind. In retrospect, it seems to just sort of fall out from the way you'd expect adaptive immunity to evolve, though.

mdswanson

Can't help but to highly recommend the recent book by Philipp Dettmer, Immune: A Journey Into The Mysterious System That Keeps You Alive. It's fantastic and very readable: https://www.amazon.com/dp/B08XTNHRR5/ref=cm_sw_em_r_mt_dp_FX...

whatshisface

What's the connection to information theory?

d0mine

On information theory [unrelated to the discussion]: both digital information (stored in DNA --4-letters) and analog information (epigenome) can be manipulated for various effects e.g., "Lifespan: Why We Age—and Why We Don't Have To" by Sinclair https://www.amazon.com/dp/B07N4C6LGR/

dekhn

sorry, I shouldn't have thrown that in there.

rubicon33

Where can I read more about this? Can you recommend a book or something?

jonnycomputer

I think this is may be one reason they used CMV infection as a control. Unless you think that the people who don't get CMV are not special, but the ones who don't get EBV are...

dm319

Yes that's a good point.

moneywoes

As someone with an autoimmune disease, is there anything I can do to prevent getting more? Iirc having one is a risk factor for others

dm319

I'm afraid this is out of my scope of understanding. Once the immune system determines something is non-self, the immune system can often self-propagate the response. It eventually enters a tolerance phase where it aims to just 'control' the threat.

There are some known modulators of the immune system, but the medical forms can be especially blunt tools (i.e. steroids). Locally directed treatment is better, and maybe in the future we'll have specially crafted cells that can inhibit a specific response for particular antigens.

There is a long and slightly-controversial link between stress (and lots of other environmental factors) affecting the immune system. I'm not familiar with the literature.

manwe150

I recently learned (also from HN) that wild-type measles can often destroy your bodies pre-existing immunities to most past threats. I wonder if we will someday be able to trigger a similar effect with a synthetic virus, wiping the immune memory, then re-vaccinate to get back immunity afterwards. But it is practically just science fiction stuff now, as far as I know.

kennethh

I had Ulcerative colitis for 20 years and managed to get rid of it by changing the diet. I used the carnivore diet, ie eat mostly meat, egg, fish (animal products). Cutting out processed foods, sugar (only 70% dark chocolate) and seed oils. I would recommend trying it for a couple of months and see if it helps, and if you do not notice any difference you have not lost anything. I lost 10% of my body weight without ever being hungry so that might be a nice side effect also.

mb_72

Crohn's sufferer here. I have lost track of the times people have said "I tried this diet, and then my Crohns / UC went away".. and then some time later their symptoms reappeared. My understanding (via own reading and discussion with my doctor) is that there is just as much evidence against as for a meat-based diet .... or any kind of diet.

As my specialist put it "if there was a common diet that cured people, we would know about it already". Anecdotally one never knows if their UC/Crohn's improves because of their diet or it's just part of the ups and downs of those diseases.

That said, I'm happy in general if I hear a fellow UC / Crohn's sufferer seems to have found something that works for them, especially something that is better for you than steroids and other treatments with severe side-effects.

Broken_Hippo

To be absolutely fair to readers: Please speak to your doctor before deciding on a diet to "cure" an illness, especially since fatty foods can trigger attacks for some folks. Ulcerative colitis has no actual cure, and this is one way one person has managed it a bit better. It might not be recommended for you.

(Sorry, i'm in this thread because I have MS, and there are lots of scam diets claiming to cure it. They don't - at all. They mostly just make folks feel like they have control).

dncornholio

Carnivore diet seems like a perfect excuse for people who don't want to eat their veggies. If you could provide any proven benefits of this diet that other diets don't provide, I'll change my mind.

Mildlypolite

As someone with an autoimmune disease I can say that this book https://books.google.it/books/about/An_Epidemic_of_Absence.h... Really helped me understand the complexity of what we are talking about. By the way he mention epstein Barr too, it seems that When you are infected is very important.

The prevalence of autoimmune diseases went up during a particular period of time while hygiene increased while other factors went missing that seems important for the regulation of our immune system.

mpreda

[this is not medical advice] Some things that may modulate the immune system are: vitamin D3, intestinal worms, exercise, diet / fasting, and gradual stimulation of the immune response ("desensitisation").

trulyme

Off-topic: interesting that we often see IANAL, but very rarely IANAD (I am not a doctor) around here. Either there's a lot of doctors here, or people are more comfortable giving medical than legal advice, which is weird, as medical advice can have very serious consequences.

johnisgood

Propolis and Cinnamomum verum are great immunomodulators for autoimmune diseases. Echinacea is sold as an immune system booster, and it is a firm nope.

Broken_Hippo

Nope. Since we aren't certain what causes most things, we can't really prevent them. (This research isn't saying they know what causes MS, to be clear).

Realistically, the best thing you can do is basic health stuff. Get activity, eat a variety of healthy foods, and so on. As you can, anyway. Mostly because this stuff improves your outcome if you happen to get another (and probably helps with the one you have - I have MS, and this basic stuff tends to help outcomes)

kortex

Helminth therapy is supposed to help moderate it. I did it to get a handle on my asthma and allergies and it worked quite well. There's various websites and support groups which detail the process and why it works etc.

There's a bit of squick factor to get over but it is worth it for the relief.

https://helminthictherapywiki.org/wiki/index.php/Helminthic_...

hda111

Had a similar thought when reading the headline. It’s like saying drinking water causes MS.

philshem

100.0% of people consume H2O. There is no control group.

birdyrooster

I guess titling the article "Multiple Sclerosis Causality" and then immediately going into EBV correlation seems like implication to me.

null

[deleted]

user90349083

For anyone dealing with an acute bout of Epstein-Barr Virus, I used 3 teaspoons a day of monolaurin for three weeks to kick it. Research monolaurin, it's fascinating stuff as an antiviral and I can personally attest to its effectiveness.

csdvrx

Or get actual antivirals. IIRC the same thing that's prescribed for HSV works on EBV

user90349083

Some people prefer God's medicine to man's medicine. To each his own

Mezzie

I have MS and my first relapse was a pretty textbook case of transverse myelitis of the sort that the EBV can cause.

I know some people have been asking about why that might be the case when a ton of people have EBV, and I think the causality may go the other way: Those of us with something wrong are more likely to both have EBV complications and MS.

There are other viruses like this as well (ones that most people get/have but aren't dangerous). I was on one medication where I needed to be tested monthly because if I got one particular (normally harmless) virus, the suppression caused by the medication meant I would probably die.

There's pretty clearly some sort of relation between the state of one's immune system + how it deals with 'benign' viruses + auto-immunity, and I'm excited to see what the future holds, but for now it's a cool confirmation of something a lot of MSers have talked about amongst ourselves for a while.

jessriedel

> I think the causality may go the other way: Those of us with something wrong are more likely to both have EBV complications and MS.

I'm unsure, but it sounds like you're hypothesizing that EBV infections does not cause MS symptoms, and that instead some some third factor causes both, so that preventing EBV infection would not prevent MS. The paper being discussed specifically considers and rejects this possibility with pretty strong evidence. Indeed, that is the main contribution of the paper. (The fact that 99% of MS sufferers have EBV, way higher than the 90% baseline in the general population, has been known for a while.)

Mezzie

That's why I shouldn't read articles instead of taking a nap. Thanks!

loudtieblahblah

There's other factors too.

All MS suffer-ers have low VitD.(as does just about everyone with an autoimmune issue).

They all have low uric acid too.

Almost all MS sufferers (same more most autoimmune) can also trace their disorder back to an extreme stress event too - divorce, loss of a loved one, falling into health anxiety, etc..

Are these causes or effects?

I'm guessing there's compounding factors.

csdvrx

Or that people who can't clear EBV may be unable to due to some deficiency that also cause them to get MS

Still a super interesting paper

roganartu

> There are other viruses like this as well (ones that most people get/have but aren't dangerous). I was on one medication where I needed to be tested monthly because if I got one particular (normally harmless) virus, the suppression caused by the medication meant I would probably die.

For those curious, I’m going to guess and say this might’ve been Tysabri (natalizumab) and that the virus in question is JCV (John Cunningham virus). After approximately two years on Tysabri, people who test positive for JCV antibodies (approx half the population of the US) have an extremely high chance of developing an often-fatal brain infection called PML (Progressive Multifocal Leukoencephalopathy).

Tysabri was originally pulled by the FDA due to PML deaths back in the early 2000s, but later got reapproved after the link to JCV was discovered. Nowadays patients get tested for JCV antibodies every 6 months. The treatment is considered quite safe now, with the caveat that if you test positive you cannot get Tysabri anymore. Most people don’t switch from negative to positive, but it happens occasionally.

Source: my wife has a rare form of MS and has been on Tysabri for about 5 years now, relapse free. Modern MS drugs are a scientific marvel.

loudtieblahblah

Monthly 3-4 day fasts - combined with a healthy diet in between (Mediterranean for ex) do wonders for autoimmune issues as well.

It was found fasting kills off old immune cells and activates stem cells to make new ones.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474734/

https://pubmed.ncbi.nlm.nih.gov/31442401/

https://www.nejm.org/doi/10.1056/NEJMra1905136

http://www.cell.com/cell-stem-cell/abstract/S1934-5909(14)00...

In plain English

https://www.forbes.com/sites/stevensalzberg/2014/12/30/can-a...

https://www.medicalnewstoday.com/articles/277860#In-mice,-pr...

2dvisio

Confirm. My brother is was on Tysabri for more than 5 and recently got confirmation of JCV. The checkup is however more regular. Blood test + MRI + symptoms check every three months, as if done less regularly would increase massively the risk. If JCV flare up is detected they’ll need to flush/wash the Tysabri away from his bloodstream.

He also got a severe mononucleosis infection before being diagnosed, and at that time we all thought that could have been the cause.

Mezzie

Bingo!

supperburg

Well said. I said the immune system should be to blame in the previous thread and was downvoted to hell. But it’s true. What’s more, it’s highly under appreciated that the immune system is extremely ancient and it does a lot more than the typical things associated with it like destroying tissue. It pulls deep metabolic levers that can make critical cells, including brain cells, latent. It can do many amazing things. In the future, the immune system won’t be known for immunity — it will be known as something like the second nervous system and will be associated with the nth great wave of medical progress when we finally conquer it and all the hundreds of diseases it causes. Diseases we don’t even have a name for now, I know for a fact.

the_decider

An immunological biomarker aasociated with MS had been discovered a few years back, but sadly nothing came of that research. https://www.nature.com/articles/s41598-017-04439-5

supperburg

I think even if we find some markers it won’t be enough. It will take a full blown revolution in how we measure human anatomy in a clinical setting. That’s why it’s taken so long.

Broken_Hippo

To be fair: I have MS. I've never had EBV with symptoms that I know of - which is absolutely normal. When folks catch it as children, there are generally zero to no symptoms. And I'm not alone, judging by activity on MS related sites.

I wouldn't take the word of "a lot of MSers" - I mean, there are folks that push the scam WAHLS protocol (diet) as a cure, too. Unless the folks are researchers, an MSer's thoughts about what causes the disease are often just as baseless as a non-MSer.

dtech

> I think the causality may go the other way

The whole point of the article is that this isn't the case.

brechmos

What is interesting is that Epstein-Barr has been reported to be related to Multiple Sclerosis since the early 1980s.

https://pubmed.ncbi.nlm.nih.gov/?term=epstein+barr+multiple+...

It is great if there is new information and if this leads to knowledge on how to reduce the chance of getting MS.

sonicggg

Cause is still not well explained. EBV is such an ubiquitous virus, more than 90% of all adults worldwide have been infected with it. Most will never know. Why is that just a tiny percentage develop MS?

malloc2048

Good question, if I am correct there is also a higher chance to develop MS if you are a woman and if you live in the northern hemisphere and some parts of Australia and New Zealand.

Also if you are of Northern European descent the risk is higher if I remember correctly.

Possibly it's a mix of many things and you have to be one of the unlucky people where that mix triggers something in the immune system and the disease develops.

I am very unlucky in that regard.

According to my doctors the number of autoimmune diseases I have is rare in a single person.

I have a sysmetic autoimmune disease (Rheumatoid Artritis) and autoimmune diseases in my kidneys, liver,thyroid, skin and mouth.

So somehow multipe times there were events in my life where a mix of things caused my immune system to turn against me.

A little off-topic, but to give an impression of how that works out in daily life, in case you are also diagnosed with an autoimmune disease.

If you are lucky, there is good medication and you will hardly notice you're ill, except for the checkups with your doctor

I also know some autoimmune diseases can (become) pretty aggressive, but n=1, most people I know with autoimmune diseases have a decent quality of life.

Fortunately, in my case also for each disease there is medication that either supresses the inflammation or the protects my body against the effects of the auto-immune response.

So I take my pills and a bi-weekly injection with a biological and I can continue to live with a decent quality of life.

Except for one important thing, my main remaining symptom is that I have a lot less energy than most people and need much more sleep.

Despite that all inflammation parameters in my blood show no signs of inflammation or activity of the disease, my body somehow loses energy to something.

This seems to be a complaint of many autoimmune illness sufferers, no signs of activity of the ilness, but more tired than before the disease came into their life.

Hopefully there will soon be more developments in this area of medicine.

supperburg

Yes, inflammatory signals can and do pull metabolic levers, something that is criminally under appreciated, and this can manifest as feeling tired somehow. There is absolutely a connection.

someotherperson

> if I am correct there is also a higher chance to develop MS if you are a woman and if you live in the northern hemisphere and some parts of Australia and New Zealand. Also if you are of Northern European descent the risk is higher if I remember correctly.

I believe this has been largely disregarded. The higher incidence rate in Europe/Anglosphere was a consequence of higher testing and accurate diagnoses, coupled with the ability to provide treatment.

killjoywashere

EBV is associated with a lot of things that involve a tiny percentage of the population. Nasopharyngeal carcinoma, Hodgkin's lymphoma. Non-Hodgkin's lymphomas. Post-transplant lymphoproliferative disease. Burkitt's lymphoma. Oral hairy leukoplakia. Related viruses are associated with other diseases, e.g. HHV-8 and Kaposi's Sarcoma, primary effusion lymphoma, and Castleman's disease.

jessriedel

Is there an estimate anywhere of the total health burden of EBV, making reasonable assumptions about causality for the diseases you describe? Would be very interesting to know so you could compare it to the risk of a future EBV vaccine.

Metacelsus

I calculated it on my blog a few months ago: Every year, it causes the loss of 4.6 million disability-adjusted life years due to cancers alone, and another ~2 million to autoimmune diseases like multiple sclerosis.

https://denovo.substack.com/p/epstein-barr-virus-more-maladi...

throwawaylinux

What are the reasonable assumptions about causality?

rewgs

Welcome to the immune system :p

Most people don't develop food allergies. Especially most adults if they don't have a family history of it/didn't have any food allergies as children. Those that do typically only develop 1 or 2.

I can't imagine how infinitesimally small the odds of this happening to me are, and yet here I am, at age 31, with nearly 30 food allergies that all activated about a year ago, seemingly overnight. No known cause, and after a year of researching the immune system and just how depressingly little medical science knows about it, I doubt I'll ever know, let alone receive a treatment that will allow me to eat like a normal person again.

And that's just one way in which the immune system can go haywire. There's MS and all the dozens of other (auto)immune issues -- so many that some don't even have a name. It is truly baffling, but the immune system has gotta be one of the single most complex systems known to man. There's a whole lot of ways something like that can break.

dd36

Pardon my ignorance, does this mean you won’t have allergies if you take an immunosuppressive drug?

scotty79

Why only a small percentage of those who contracted polio got paralysis? Interesting, but for now let's settle on eradicating ebv to hell

jessriedel

This question, though very worthwhile, doesn't necessarily need to be answered. Vaccines for EBV are under development. If we stop most EBV infections, we can stop most MS.

lamontcg

Doesn't help you if you've already got a persistent EBV infection though, and the host immune response to EBV may be something that you want to avoid stimulating if you've already got it in you and can't get it out.

Something like CRISPR/Cas9 editing may be the way to treat persistent EBV and other herpesvirus infections.

bluGill

Maybe, though it appears that covid vaccines help clear long covid, so maybe not. Until we have a vaccine we cannot study this to see how or if it works.

Metacelsus

Yeah, but will the vaccines be effective? EBV is amazingly good at immune evasion. Prior antibodies don't protect against re-infection.

sonicggg

Vaccine is no guarantee though, just look at Covid. DW was recently covering breakthrough cases that led to Long Covid. You're speculating now.

boondaburrah

Right but when was the last time anyone you know got polio? Vaccines aren't 100% effective but if we can get the average susceptibility to the virus in the population down far enough (even though it'll never be complete) there's a threshold where the virus can have a hard enough time hopping that it really makes a difference.

bagacrap

I don't see where gp assumed a vaccine will be effective. Note "if".

howinteresting

This study appears to suggest that MS is essentially "long Epstein-Barr." Terrifying if the same pattern holds for covid, given the number of people who have some sequelae (the most conservative estimates are 2-5% for "serious" post-viral symptoms, which would be hundreds of millions of people worldwide). There will be an extraordinary amount of suffering, not to mention radical shifts in economic and public policy.

kmeisthax

There's another paper from June of last year[0] that proposed a long COVID explanation: Epstein-Barr reactivation. I haven't seen any follow-up work yet, but if both that and this paper have any predictive power to them[1] we might start seeing a cohort of "long long COVID[2]": people who got COVID, didn't recover, and then progressed to MS.

[0] https://pubmed.ncbi.nlm.nih.gov/34204243/

[1] I'm particularly worried about the "EBV reactivation" theory as COVID-related studies have been used as a vehicle for many medical frauds.

[2] As per ISO standards long long COVID must have an infection duration represented with at least a 64-bit machine integer

vintermann

That sounds unlikely. Epstein-Barr is a herpesvirus, and it's persistent - once you catch it, it stays latent in your body and you'll shed it through your saliva periodically for life.

As far as I can find, coronaviruses have no way to pull that trick. Once your immune system gets rid of it, it's gone and not coming back unless you're infected again by a sufficiently unrecognizable relative.

Tagbert

Like my uncle, Oscar? He looks nothing like anyone else in the family and looks out of place in family photos. I’m pretty sure he is antivax, too.

f38zf5vdt

Coronaviruses do a weird thing where their viral RNA persists in cells long after the initial infection. [1] No one knows if this has a bearing on long COVID or not.

[1] https://www.nature.com/articles/s41592-021-01145-z

jonnycomputer

Yeah, I don't trust the viruses not to do sneaky shit. Not at all.

vintermann

It's not a terribly weird thing for a virus to do, but as far as I know (just an interested amateur) coronaviruses can't use this to stay latent.

f38zf5vdt

We don't really know. A recent manuscript submitted to Nature shows minute persistence in various tissues as long as 230 days or more post-infection. [1] RNA is fragile, if the infection is completely cleared or not integrated into the genome in some way we would not expect it to persist.

[1] https://assets.researchsquare.com/files/rs-1139035/v1_covere... (Figure 1)

howinteresting

I would be hesitant to generalize from existing coronaviruses to SARS-2. As the sibling comment points out, SARS-2 has been shown to persist in every organ of the body well after initial infection.

axg11

The study really doesn't suggest that. All it suggests is that EBV seropositive people are much more likely to develop MS than the seronegative minor population.

As for long COVID, the data quality is very variable. I'd like to see a controlled study that compares recovery from COVID vs. other respiratory viruses.

howinteresting

It's pretty clear that the causal explanation is the only reasonable one here. (Besides, at least for covid, not everyone who contracts the virus develops antibodies for it: https://journals.asm.org/doi/10.1128/Spectrum.00904-21 )

There's a reason I quoted conservative estimates of long covid. The 2% is from this ONS study: https://www.ons.gov.uk/peoplepopulationandcommunity/healthan.... The high end of estimates is 10-30%, which would mean the end of our current era of civilization.

stefan_

There are lots of viruses that persist forever. You can get chickenpox as a kid then die of shingles as a retiree. Measles might give you only mild symptoms then 6-15 years after reactivate and cause Subacute sclerosing panencephalitis (SSPE), a fatal brain inflammation with all the interesting symptoms that implies (starting out with mood swings progressing into dementia, muscle spasms and blindness).

Think of this the next time some brain dead person starts talking about the "unknown long term effects of the vaccine" - we know what has long term effects, and it's freaking live viruses!

reedf1

Terrifying - I was EBV positive 4 years ago. It does not mention an association between EBV severity and MS, but I was very symptomatic and had post viral fatigue for around a year. I had no idea about the MS association!

danuker

> According to epidemiological studies, the EBV is estimated to be positive in more than 90% of the world's populations

- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008310/

> A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population)

- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720355/

Given that you have EBV, I guess you're in the unlucky 90%, increasing your odds from 359 in a million to a ...whopping... 399 in a million.

BobbyJo

Since the risk for the non-EBV group is 32x less, you'd be increasing your odds from like 11 in a million to 399 in a million no?

andi999

If you knew you were negative yes, if the status was unknown then not.

arbuge

Calm down... from the article:

"Note, though, that EBV would then be in the "necessary but not sufficient" category. There's something about the interaction of particular human immune systems with EBV infection that pushes things over into the pathological state of multiple sclerosis, and we don't really know how to identify these people. But that fits with what we know about infectious disease in general - everyone's different. The situation with Guillian-Barré is similar - a small number of people tip over into neurological pathology, for reasons unknown, and that one also often seems to follow some sort of viral infection."

jka

That's a good quote, thank you.

About the use of "calm down" as an instruction: while your sentiment is good (to reduce another person's anxiety), it's not always possible for someone to follow that when it is received as an instruction. It's tricky to estimate other people's emotional state based on text, and for them to infer your tone. I'm overexplaining and sure that you probably understand all that; but it feels worth mentioning.

dwmbt

> About the use of "calm down" as an instruction: while your sentiment is good (to reduce another person's anxiety), it's not always possible for someone to follow that when it is received as an instruction.

this is a pet peeve of mine. something i picked up when i was a counselor at a special needs camp was the idea that everyone (regardless of where you lie on any spectrum) has a unique sensitivity to criticism. it's important to NOT treat people how you would like to receive criticism, but to assess how you think they would best consume and digest it. obviously, this is extremely difficult on the internet and i'm just nitpicking but i had an altercation with my sibling earlier when they told me to 'calm down' so i'm still on edge about it.

i'm sure OP doesn't need to hear this but typically i find that a good alternative is to nudge someone into rationality. not to say that the parent comment is irrational, but when you simply show someone why they may be overreacting, they may very well 'calm down' all by themselves. if said person refuses to acknowledge your rationale, it's likely they aren't welcome to any criticism at all and won't be 'calming down' in any capacity.

jonnycomputer

True. My first reaction to the directive, was that it was rude. Reading more of the context attenuated that impression, but I still think it could have been phrased less ... paternalistically?

garganzol

There is one more condition you may be interested in: CFS/ME. It manifests itself primarily as a chronic fatigue and is believed to onset after a trigger event: virus, intoxication, hypoxia, stress, and the like.

I talked to some people with MS and most of them told me the same story: the trigger event, followed by some time, then onset of a full-blown MS.

I wonder: are those diseases really different? Or maybe this is the very same disease but with a bit different outcomes: myalgic encephalopathy vs sclerous plaques. Both are driven by the inflammation, both have the same initiating sequence.

What leads me to strongly suspect that it may be just different manifestations of the same disease is the involvement of mitochondria in both MS and CFS/ME.

thewebcount

And along with CFS/ME, also look up POTS, MCAS/MCAD, and EDS. My wife had a very bad bout of mono in late high school and 15 years later developed POTS, MCAS, and what the rheumatologist called "unspecified connective tissue disorder," which seems like a mild case of EDS. After 10-15 years of trying treatments, she's significantly worse off. :-/

There are tons of people (mostly women) out there with this set of conditions, and they're only starting to be taken seriously. It's a set of life-altering conditions and dealing with the medical system when you have it can be infuriating and exhausting. I hope you don't have any of these things.

mturmon

My wife also has MCAS, POTS, and a connective tissue disorder that is not at the level of EDS. Was diagnosed about 4 years ago and is on treatments to suppress some immune responses, that has been helpful at taking the edge off some symptoms. It was like tumblers clicking into place when she saw a specialist and got the diagnosis, so many rather disparate, long-term symptoms all from the same cause.

garganzol

POTS, MCAD-like (hyperlipidemia) and inflammatory conditions are triggered by CFS/ME as well.

I am really puzzled: are we dealing with the same thing but under different names?

For reference, NSAIDs combined with high-dose vitamin therapy help to resolve those conditions in people with CFS/ME.

kennethh

In Bergen in Norway we had a big outbreak of Giardia parasite and a lot of people got CFS/ME after that. The Giardia was big because the parasites came into the drinking water from one of the water sources. I myself had this for of this for many years afterwards but one do not notice it since before you get rid of it. I was able to function normally but totally lacked energy, and everything was a chore. It was like the feeling the first time one drinks coffee and experience the way the fog clears up.

Conclusion. The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598369/#:~:tex....

Also very impressed with google when searching for: giardia leads to CFS

radicalbyte

I have this pet theory that CFS/ME is what a lot of long-covid patients are suffering. I knew a few people who have been affected by it, and it really limits them. Just as long-covid seems to.

garganzol

I came to the same conclusion as well. Moreover, I was somewhat successful in healing post-viral CFS/ME using the therapy targeted at mitochondria with large doses of B1 and B3 vitamins [1].

[1] https://news.ycombinator.com/item?id=29138006

rmind

Back in 1980s, there were proposals for a "chronic mononucleosis" or "chronic mononucleosis syndrome" as a diagnosis / standard disease. There were very comprehensive studies trying to investigate the patients who had chronic fatigue and other long lasting debilitating symptoms. After a good decade of studies, the research community found that this group of patients is very consistent (their complaints, symptoms, etiology), but failed to prove EBV as a cause (although the studies did not disprove it either) or at least come up with a clear serological diagnostic criteria. So, in 1990s they decided to define a generic Chronic Fatigue Syndrome (CFS) as a standardized disease. Other viruses and pathogens can cause CFS/ME and a broader definition would sometimes include even psychosomatic patients, so as a result CFS/ME has been quite discredited.

Diagnostic techniques evolved and research progressed. In the recent decade, new studies are very close to proving that EBV is indeed a likely cause of CFS/ME (well, one segment, as there are other causes too). Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/

lalaland1125

One important thing to note is that EBV is extremely prevalent. Almost everyone gets it eventually and very few of those people develop MS.

jonnycomputer

But a lot of people don't really develop severe symptoms either, right?

marvin

When I had it, my doctor said that if I was a professional athlete, the standard outcome would be to just consider the current season lost and switch focus to getting well again in time for the next.

I was relatively useless for two weeks and then spent the next four months getting back to my normal energy levels. "Severe" is a question of definitions, I think. I wouldn't consider that kind of illness severe, but it certainly put a dent in things for a while. Properly inconvenient, I'd say. I think this degree is pretty common.

cestith

Some develop no noticeable symptoms and many develop mainly annoying ones for a few weeks to a few months. I had the misfortune to develop symptoms from infectious mononucleosis shortly after minor surgery. My GP and surgeon kept giving me antibiotics and sending me back to uni. Finally after several months of fatigue, nausea, and depressed appetite I wandered into campus health jaundiced with a 104º F fever and a temporarily enlarged liver. I ended up withdrawing from that semester and retroactively from the previous one. I was ordered into a month of bedrest and half a year of decreased physical activity while recovering. So I guess we could say there's a wide range of severity, partly depending on how soon it's addressed.

Broken_Hippo

Many if not most folks dont' even realize they get it because they catch EBV as a child. In children, it generally causes no symptoms or symptoms so mild that they are dismissed as a normal childhood virus. You know, the sort you miss 2 days of school for and then go on. This is the reason most folks don't know they've had it.

When we get older - teens and adults -, we are more likely to have it develop into mono or other things that realistically make your life difficult for a while.

shadowgovt

If you're EBV-positive, you're in good company... It infects something like 90% of the human population.

Makes me wonder how many virii are out there that haven't been identified by modern medicine because their spread vector is so low-impact that they never even trigger symptoms. A virus like that would become real indistinguishable from "behavior of the human body" in not very much time if its infectivity was high.

csdvrx

> A virus like that would become real indistinguishable from "behavior of the human body" in not very much time if its infectivity was high.

My weird theory: how can we know then if aging (or its acceleration or the diseases usually linked to it) isn't the result of some infection that's super contagious and infects 100% of the people,

raylad

It's not weird, it's the same idea I had back in the 1970s, but at that time things like retroviruses weren't known or understood.

Now we know about endogenous retroviruses, and yes, they have infected everyone (going back millions of years) and yes, they do become more active in aging and are responsible for cancers and causing cellular senescence via DNA damage through retrotransposon activity.

You can inhibit them with some of the same anti-retrovirals that work on HIV. Or nutritionally what may work is: high doses of cyanidin plus NAD precursors to stimulate SIRT6, which normally prevents at least one of these endogenous retroviruses, LINE1, from being expressed.

inter_netuser

Because it's very unlikely the same pathogen or disease would affect shrimp and humans in the exact same way.

axg11

Great question. A related question: how many undiscovered viruses exist that are beneficial to the host?

bigbillheck

There's the anelloviruses which are at least as prevalent and nobody really knows what they do.

f38zf5vdt

If you're going to develop MS as an adult after getting EBV mononucleosis, it's likely that it will be soon (5-10 years) after you have the initial infection as an adult. There's only a long delay in children according to one study. [1] Every passing year the probability of getting MS should decay after that.

Female sex and EBV mononucleosis during adolescence are the biggest risk factors.

[1] https://nn.neurology.org/content/4/3/e308

Broken_Hippo

Scores of folks with MS never had mono. I'm one of those. It isn't mono that is the risk factor, but EBV itself.

config_yml

Interesting. My sister and I both had mononucleosis before puberty, and she was diagnosed with MS in her late twenties.

nefitty

The article says EBV is prevalent and is probably necessary but not sufficient for MS. If I was in that position I would look at my gene test results for any markers that correlate with MS. The more of those markers, the more intensely I would prioritize following relevant interventions.

nradov

What are the relevant interventions? Which genes correlate with MS?

nefitty

That's the independent study part. I wish I could be more help but that research is time and money intensive, and not guaranteed to be fruitful. It also involves review of multiple studies, sometimes several dozen. Then it's about seeing which ones are relevant to an individual's specific genetic mutations.

I'm currently going through dozens of reports from SelfDecode, and that's after massive amounts of work on their end. I think I'm out a few hundred bucks so far, but it is an amazing service. I will soon seek their genetic consultation service, which is about $1k, and their lab testing service.

cjensen

EBV causes more severe symptoms the older you are. So everyone here who remembers getting it and it being terrible? That's because you got it as an adult. If you get it as a kid, it can be asymptomatic.

I got it at 36 and had a fever that leveled me for 3 weeks. Between "wait 1 week before bothering your doctor" and multiple rounds of tests, they didn't even diagnose it as EBV until the 3rd week.

csdvrx

I got at 21 IIRC and I was in bed for a few weeks and the doctor started fearing I had a blood cancer or something given how abnormal the tests were until he finally got the idea to test for EBV and it came back super positive.

Never before was I so happy to get tested positive for something lol

It's been a few years and I think I'm fine but due to hedonic adaptation etc maybe for all I know I operate at like 70% of my previous capacity and don't even realize it

So I'm super interested in all that new research and I can't wait until we get mRNA vaccines against EBV!!

Miner49er

From my understanding, the leading theory of what causes autoimmune diseases is viruses. The immune system responds to the virus and ends up mistakenly attacking the body as well. This seems to support that, and shows that different viruses cause different autoimmune diseases.

More info: https://www.nature.com/articles/d41586-021-01835-w

f6v

I’ve been reading recent research on MS and other autoimmune conditions. I also study APS1 in my PhD at the moment (caused by AIRE gene deficiency). I’m definitely not an expert, but I don’t think it’s a leading theory. As always in biology, autoimmune diseases probably have dozens different causes. Many of them might be environmental or genetic. Better yet a combination of the two.

jjcon

Any thoughts as to why autoimmune diseases are (or at least seem) more prevelent in the 1st world?

epgui

Broadly speaking, the hygiene hypothesis is the current leading explanation.

To make an analogy, in AI/ML terms, it amounts to a training set problem: you're not exposed to a diverse enough set of microbes and pathogens, or you're exposed to a biased sample, or you're not exposed to enough microbes.

Your immune system's role is to act as a classifier to discriminate between good and bad, self and non-self. When you have a bad training set, you increase the odds that good things will be identified as bad, or that self antigen will be recognized as foreign.

colechristensen

Four candidates: hygiene, better diagnostics, different exposures, longer safer lives.

dham

Parasites. When you start getting rid of parasites in 3rd world communities, auto immune issues start to crop up. It's thought that since the body isn't fighting off parasites then it sits idle and starts attacking itself. It kind of makes sense from a purely evolutionary perspective. There's actually been treatments for some auto immune diseases that involve giving a relatively harmless parasite to people.

Broken_Hippo

If your country doesn't have a medical system that will detect such things in the general population and does not have a system to get the numbers for statistics, how are you going to know how prevalent something is?

We don't know how common lots of things are in 1st world countries either, simply because we don't track.

f6v

They’re just probably under-diagnosed in the 3rd world.

atombender

There's also some really compelling evidence that psoriasis is caused by bacteria. Psoriasis is often described as autoimmune, but is probably better described as immune-mediated disorder. Unlike autoimmune disorders like MS and lupus, psoriasis doesn't involve the body "attacking" itself.

Specifically, streptococcus bacteria such as Streptoccocus pyogenes, also called Group A Streptococcus, which is primarily responsible for rheumatic fever and scarlet fever in developing countries, and more commonly known in the West for causing strep throat (streptococcal pharyngitis).

We already know with almost certainty that S. pyogenes triggers a form of psoriasis called guttate, which in 60% of cases resolves on its own within 1-3 months. But in the remaining cases, it turns chronic. It can also come and go: spontaneously resolving and then coming back a few months after.

What's particular about strep is that it appears that it can lie dormant in the body. The tonsils of psoriasis sufferers have been found to contain strep bacteria, and a recent meta-study concluded that a tonsillectomy can significantly improve psoriasis in about 70% of patients who undergo the procedure; so it's likely that the tonsils act as a reservoir for continuous reactivation. (Apparently, people who have a tonsillectomy as a child are also less likely to develop psoriasis.) Strep bacteria are also thought to evade serological detection by hiding in biofilm, from which they periodically emerge to reactivate the immune response.

As to why only some people develop psoriasis, the explanation might be some kind of genetic predisposition. Psoriasis is often explained as maybe being caused by "cross talk" between the adaptive and innate immune systems.

Some papers:

Streptococcus pyogenes-induced cutaneous lymphocyte antigen-positive T cell-dependent epidermal cell activation triggers TH17 responses in patients with guttate psoriasis https://pubmed.ncbi.nlm.nih.gov/27056267/

Group A streptococcal pharyngitis: Immune responses involved in bacterial clearance and GAS-associated immunopathologies https://pubmed.ncbi.nlm.nih.gov/28951419/

Psoriasis, chronic tonsillitis, and biofilms: Tonsillar pathologic findings supporting a microbial hypothesis https://pubmed.ncbi.nlm.nih.gov/29554401/

Psoriasis, chronic tonsillitis, and biofilms: Tonsillar pathologic findings supporting a microbial hypothesis https://pubmed.ncbi.nlm.nih.gov/29554401/

Tonsillectomy and the subsequent risk of psoriasis: A nationwide population-based cohort study https://pubmed.ncbi.nlm.nih.gov/33548305/

Mechanisms of microbial pathogenesis and the role of the skin microbiome in psoriasis: A review https://pubmed.ncbi.nlm.nih.gov/30981296/

deltaonefour

This is a bit off topic but I have a question about causality.

Is causality really a fuzzy concept? For example I assume if action A causes event B I assume the connection is 100%. Can we really say that action A has a 30% chance of causing event B?

I ask because the more I think about it, when someone says action A causes a 30% chance of event B occurring what he is technically saying is action A is one causative factor that must occur and that we're missing information about other causative factors.

In the case of this article. A causative link is established between EBV and MS to a fuzzy probable degree. This seems to me that technically what's actually occurring is that a fuzzy causal link simply means that there are other causative factors we don't yet know about, and likely this is a specific type of immune system that reacts to EBV in a certain way.

Would my assessment be accurate? All causal connections are either 100% and any fuzziness just means we're missing information about other joint causal events that must occur to trigger the outcome. Does anyone who's a statistician know?

echelon

> we're missing information about other causative factors.

Welcome to biology.

Perhaps EBV is particularly immunogenic, but it has to reactivate in the presence of CD8+ T-cells or CD20+ B-cells along with some other self-signal or co-infection. Perhaps there's a chain of immune signaling that must happen upstream in other immune cell populations.

Perhaps other agents can trigger autoimmune behavior in these cells, and EBV isn't strictly required. Maybe other viruses in the herpesvirus family (HSV, zoster, etc.) There could be more than one set of causes, and they might not even look similar.

In the crazy absurd limit, maybe nothing at all. Maybe autoimmunity sporadically arises with no causal agent. Random radiation hits the cell at the wrong time.

All or none of these could be the case. Diseases can have a multitude of causes, sometimes with complex interactions and interdependencies, sometimes not. With cancer it's a progression of increasingly worse state changes, and that could be the case here too.

dataflow

> Is causality really a fuzzy concept? For example I assume if action A causes event B I assume the connection is 100%. Can we really say that action A has a 30% chance of causing event B?

The world is probabilistic at the quantum level so I don't see how it could be otherwise.

> I ask because the more I think about it, when someone says action A causes a 30% chance of event B occurring what he is technically saying is action A is one causative factor that must occur and that we're missing information about other causative factors.

To my knowledge this has been physically disproven: https://en.wikipedia.org/wiki/Hidden-variable_theory#Bell's_...

(Note I'm just responding to your philosophical question, not the biological one. In particular I'm not suggesting anything about the practical relevance of quantum effects to the biology discussion here, or lack thereof.)

beaconstudios

this doesn't occur above the quantum level though.

peter303

There was a similar debate in the 1880s. Dr. Robert Koch claimed some diseases were caused by bacteria and developed a procedure to prove it. The germ theory of disease was controversial until then.

Its suspected several diseases without known causes may be caused by a bacterium, virus or protein. But lack the evidence to satisfy the Koch postulates. These diseases include some cancers and many human nervous system diseases.

sva_

> All causal connections are either 100% and any fuzziness just means we're missing information about other joint causal events that must occur to trigger the outcome.

I think one theory is, that the immune system has a way of approximating the surface of a protein, and in this way recognizes what to build antibodies against. This process could be a source of fuzziness as the "protein signatures" of a virus may vary from person to person. There is also the question how those signatures are stored and retrieved in the immune system, and why they -presumably- lead to the immune system misrecognizing myelin sheaths as a threat (in some people, some of the time.)

csee

This is more in the domain of philosophy than statistics.

I wrote something in response, but then saw that the Wiki article on causality was far better than what I wrote, so have a look at that.

https://en.wikipedia.org/wiki/Causality

https://en.wikipedia.org/wiki/Necessity_and_sufficiency

gwern

Is it helpful to ask about 'percentages' here? Is oxygen 0% or 100% of the cause of you posting here? What about gravity?

Whenever you have a causal question, often taking a Pearlean perspective and asking about interventions would be more useful. For example, there is an EBV vaccine being worked on right now. If you believe OP that EBV infection is a necessary but not sufficient condition for 90% of MS cases, then it would be reasonable to say something like "if we intervened by making everyone got the EBV vaccine, then there would be ~90% fewer MS cases than in the counterfactual universe where everything else was the same but no one got the EBV vaccine." That sounds much more interesting and meaningful to me than talking about how "EBV is necessary but not sufficient".

beaconstudios

simple, 1:1 causality (if I flick a light switch, the light turns off) is not fuzzy at all. Complex causality is more complex (obviously) and most things in real life have complex causality.

deltaonefour

In science nothing can be proven. That means in order to to prove that light switch turns the light off you must flick the switch and observe the light turning off infinite times.

If in one of these infinite observations flicking the switch off turns the light on your hypothesis is disproven. Hence disproof exists but proof is the domain of maths and logics. From this perspective 1:1 causality cannot be verified to exist.

mactournier

Contrary to the HN title, the paper is not about causal inference, it is a case-control study. A good primer on the limitations of case-control studies can be found here: https://www.medicalnewstoday.com/articles/280936#limitations

letmevoteplease

The abstract of the study states, "These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS."

axlee

Your contrarian approach is detrimental to proper research. Authors have found a very strong link that cannot be explained by any other risk factors. What risk factors are you suggesting they should look into?

aljungberg

The parallel to Guillan Barré Syndrome seems intuitive. MS and GBS are both autoimmune disorders which damage myelin. MS is slower and chronic while GBS is acute and rarely relapses. What if MS is a low grade persistent immune response to a chronic viral infection such that those bad antibodies are created in small amounts indefinitely?

clord

I wonder if MS is like the EBV version of shingles: if you don't get it early, when you do, it's a much worse disease. Most people pick it up early, but those who manage to avoid it and then get it late are in danger. Another instance of hygiene hypothesis.

vintermann

MS isn't, but yes, Epstein-Barr virus is more serious if you first catch it as an adult. That will likely knock you out with mononucleosis, a.k.a kissing sickness, for a few weeks. Fatigue can linger a lot longer.

latortuga

Definitely my experience. I had it as an adult at 26 and it absolutely knocked me out for weeks. I lost a ton of weight from having no appetite and having a constant sore throat. Sleeping was also terrible because I couldn't breathe easily. I think I missed 3 or 4 weeks of work and even when I started back I could only work half days for awhile at my not-strenuous desk job.

null

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sabujp

I was wondering what the genetic factors are that cause EBV to push people to get MS and found this excellent paper [1] (see the genetic susceptibility section).

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334604/

[2] https://www.google.com/search?q=genetic+factors+that+cause+E...