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The best evidence yet that immune system problems can cause ME/CFS? Simon M blog

Simon

Senior Member
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Monmouth, UK
The best evidence yet that immune system problems can cause ME/CFS?

Human leucocytes Antigen (HLA) proteins play an essential role in helping the immune system to recognise pathogens. This new research is easily the best study yet of HLA alleles (gene variants) in ME/CFS. It finds links between at alleles of least two HLA genes and ME/CFS. And since the illness can’t change (HLA) DNA, the link must be that the alleles must play a causal role in ME/CFS. So this evidence that the immune system plays a causal role for at least a subset of ME/CFS patients. The finding needs replication.

hla t cell.jpg



Does ice cream cause sunburn? The evidence for this is that many people who buy ice cream also get sunburn. Of course, ice cream doesn’t cause sunburn, people buy ice cream and get sunburn on sunny days. But this illustrates a problem faced by researchers: just because two things occur together is no guarantee that one causes the other.

Take the example of cytokines, immune messenger molecules, in ME/CFS. Researchers have found abnormalities in the level of several cytokines, which could be evidence that problems in the immune system are driving ME/CFS. Equally, the cytokine abnormalities could simply be the result of ME/CFS or just a general effect of being ill.

However, genetic studies provide a solution to this cause-or-effect problem. When genetic differences are linked to an illness, it is evidence that the gene differences play a causal role. The reason is that we are born with our genes and ME/CFS develops much later: since genetic differences come first they must play a role in causing the illness...

Read the full blog
 

joshualevy

Senior Member
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158
If, as you say, that is the "best evidence yet that immune system problems can cause ME/CFS" then I think that theory is dead.

There are (at least) three fatal problems:

1. The evidence doesn't even rise to the 80/20 rule. This is a rule of thumb that the minimum evidence to support causality is that 80% of the people who have the disease have the purported cause, and that 80% of the people who don't have the disease also don't have the purported cause. This research is well below that. It's a non-starter.
2. There is no confirmation. I'm not even holding out for independent confirmation, even these same researchers have not done a larger confirmation study. If this were a treatment, it would require about four studies to be confirmed. I'm not asking for that, but without a second study, there just isn't anything there.
3. Although I agree with you that the study results can not be caused by a ME/CFS -> HLA pathway, that does not show that it must be a HLA -> ME/CFS pathway. It very well could be a [Something else] -> HLA and ME/CFS. That is, that HLA and ME/CFS are both caused by something else. Put a third way, that HLA is a marker for ME/CFS, but not a cause.

And here are some bonus problems:

4. On an ethical level, there is no evidence that this trial was ever registered, If so, then it would be an example of "results swapping". It looks like the researchers patched together samples from four different sources. The ME/CFS patients came from three different studies. Only one is listed, and that one did NOT include genetic testing, so that would make it "results swapping". (The other two don't have a registration listed, most would consider that "results swapping" unless the authors forgot to list the registration, but that seems unlikely.) The control group came from a fourth source different from the other three.
5. The patient group(s) and the control group came from different sources. This should be a big red flag! It is the same mistake that resulted in the XMRV fiasco. When blood samples come from different sources they often test out differently because of storage methods, differences in sources, age, etc.
6. The study was not blinded. Maybe not fatal by itself, but if you've only got one study, and it's not even blinded....

I could go on, but you get the point. This study is not strong evidence of anything, except (maybe) that more research is needed. If they get a second, or even better a third, study which fix the mistakes listed above, then there will be something.
 
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Simon

Senior Member
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Location
Monmouth, UK
So this might explain- under 20% of the victims, but not the other 80%?
Certainly it will only explain a minority. But this is only looking at one part of the immune system. The proposed GWAS will look across the whole genome and hopefully find more genetic links.
Might be that the 80% acquire something similar rather than it being genetic.
As the blog says, it won't be one gene (version) causing the illness, as in cystic fibrosis. but increasing the risk. It could be that the HLA alleles increase the chance of a severe infection from particular pathogens - which would be a genetic-environmental interaction. This is just one clue that will hopefully lead to understanding what is going wrong. And there is unlikely to be a single cause.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
There are (at least) three fatal problems:

1. The evidence doesn't even rise to the 80/20 rule. This is a rule of thumb that the minimum evidence to support causality is that 80% of the people who have the disease have the purported cause, and that 80% of the people who don't have the disease also don't have the purported cause. This research is well below that. It's a non-starter.
Not heard of that rule but bear in mind that
a) ME/CFS may well have many causes - it's unlikely that 80% of people with the illness will have any factor.
b) Genetic studies are providing small clues (though causal ones) and this only looked at one part of the immune system. A more comprehensive look should provide more clues.

2. There is no confirmation.
Which I stress throughout the blog, though as I'm sure you read at the end, Ron Davis is also working on HLA genes. However, 458 patients makes this one of the largest ME/CFS studies to date.

3... It very well could be a [Something else] -> HLA and ME/CFS. That is, that HLA and ME/CFS are both caused by something else.
Would love to hear what you think is causing the HLA allele to change! That's the thing about genetic studies: the allele comes first (and doesn't change) so it is evidence of causality.
 

Learner1

Senior Member
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6,305
Location
Pacific Northwest
I'm not sure what you've proved here.

It's one thing to have certain gene mutations, but other genes and environmental factors lead to their expression.

A lot of us absolutely do have immune system problems which can be found by doing thorough lab testing. And we respond to various treatments. But we also have a variety of infections, various toxicities, biochemical imbalances, structural issues, coagulation problems, hormonal imbalances, and mitochondrial dysfunction.
 

joshualevy

Senior Member
Messages
158
I probably should have put my point #5 in the "fatal problems" part of my post.

Not heard of that rule but bear in mind that
a) ME/CFS may well have many causes - it's unlikely that 80% of people with the illness will have any factor.
b) Genetic studies are providing small clues (though causal ones) and this only looked at one part of the immune system. A more comprehensive look should provide more clues.
Those are generic excuses that can be used for any research that comes up with tiny results. Sure, it is possible. Any research that comes up with a result too small to be interesting could use these excuses. The point of research is to design trials that don't have these problems.

Which I stress throughout the blog, though as I'm sure you read at the end, Ron Davis is also working on HLA genes. However, 458 patients makes this one of the largest ME/CFS studies to date.

You did, and you were right to do that. But it conflicts with your overall tone and your headline. For research of such low quality, I think you should point out that it is not confirmed, but also have a better title, and a more appropriate tone. (Appropriate to the low quality of the research, as described by points 4, 5, and 6 above.)

Would love to hear what you think is causing the HLA allele to change! That's the thing about genetic studies: the allele comes first (and doesn't change) so it is evidence of causality.

I don't think it changed at all; I think it was always different because of my point 5 above. "The patient group(s) and the control group came from different sources." Since they came from different sources, it is not too surprising that their HLA alleles were a few percentage points different (and that really is all these guys found).

The proper headline for this result is: "Different groups of people have slightly different HLA allele levels." It is a nothing result.
 

HABS93

Senior Member
Messages
485
This is the definition of Sarcoidosis which I have. I've broken it down to the cytokines response to an infection of any sort that the lympnodes inside them cannot get rid of such infection. Therefore you go into a learned sick behavior. It's not the infection that's causing the CFS symptom's it's the response of the bodies immune system. Problem is in sarcoidosis is you are stuck in thatloop. I assume CFS is a similar loop. Hence why I thought I had CFS. Cytokines can actually cross the BBB and block nerutransmitters signalstoo. This causes Depression and anxiety . Que in the anhedonia. They say TNF-ALPHA can stop the response from being strong. However , this can cause Lymphoma later in life.
This is how far I've gotten too. If anyone has more in-depth analysis I would really like to know!!