5-HT autoimmunity associated with immune/inflammatory probs & bacterial translocation in ME/CFS

[Simon]

New, from Michael Maes:

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation

On the face of it, a spectacular finding, with positive autoimmunity in 61% of 117 ME/CFS patients (Fukuda) vs 14% of Chronic Fatigue controls (great comparison group) and 6% of healthy controls. But I would want to read the full text before commenting further. 5-HT is serotonin, an important neurotransmitter.

Abstract

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.

Methods
We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale).

Results
The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.

Discussion
The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.

 

[Marco]

Hi Simon

Looks this follows on from his 2012 paper that found elevated 5HT antibodies in depression :

Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression.

The incidence of anti-5-HT antibody activity was significantly higher in depressed patients (54.1%), and in particular in those with melancholia (82.9%), than in controls (5.7%).

http://www.ncbi.nlm.nih.gov/pubmed/22166399

So not an insignificant finding (if confirmed) but not a specific one.

 

[snowathlete]

Intriguing.

 

[Gijs]

We will never hear form this findings again. At this moment there are found so many things how does it fit the puzzel....

 

[Valentijn]

Fascinating stuff. My serotonin (among other things) is very low in red blood cells, but trying to supplement anything to raise it or taking an SSRI makes me feel absolutely awful. But I'm not sure if my reaction makes sense in the context of 5-HT autoimmunity Will try to read the whole article.

 

[Enid]

Very interesting - my brother himself a Doc overseas and getting more investigations than we in the UK (with a similar illness) was diagnosed with an autoimmune condition. Though I do suspect some possible contributing genetic predisposition/weakness say, in our cases too.

 

[alex3619]

We have already heard about this kind of thing many times - this is an evolving research, not something novel. Further it fits leading hypotheses of ME, especially any involving "leaky gut" which is less leaky than a failure of detox. The links between LPS and other issues in ME are growing, and I want to blog on this later. Further, we know from other Maes research (presuming its validated) that we have high levels of a range of auto-antibodies, rather than for a specific auto-antibody.

I have hypothesized that one possible mechanism for post viral (actually many pathogens that can infect the gut wall or liver) fatigue to turn to ME is a failure of LPS detox, resulting in prolonged LPS in the blood stream. Thats an emergency signal to the immune system, it goes nuts.

As always though, the devil is in the detail and in validation. We need the full paper.

 

[alex3619]

I have just had my first glimpse at the full paper. I need to read it in detail which may take a while. However they have shown that the cytokine abnormalities may split CFS patients into 5HT autoimmune patients, and those without. Is this a natural split in CFS, or an artifact of the study? I don't know, but its worth finding out. I wish this study had also looked at LPS levels ... I suspect a large part of the problem is LPS.

 

[Bob]

Very interesting research. I'm looking forward to reading more about this.

My initial thoughts are that 5-HT autoimmunity might affect cellular 5-HT levels, which could perhaps cause widespread disruption for the body.

Note that 5-HT (Serotonin) isn't just a neurotransmitter, and it has many functions beyond simple mood regulation.
Wikipedia says that serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS).
It goes on to say: Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements, and: Serotonin also has some cognitive functions, including memory and learning.
And serotonin affects sleep, and is involved in sleep regulation.

It is also found in platelets, and is involved in blood clotting, and is a growth factor in some cells in which it is involved in wound healing.

So although the issue of serotonin instantly raises question marks over its implications in terms of a psychiatric illness, serotonin has many complex functions beyond mood: e.g. gut regulation, sleep regulation, blood consistency and cognitive function including memory.

There's much more about it here:
http://en.wikipedia.org/wiki/Serotonin

 

[Bob]

I'm hypothesizing that 5-HT autoimmunity will result in lower cellular 5-HT levels. But that might not be the case, and maybe my thinking is naive and far too simplistic.
I know I'm not making any real scientific comparisons here, but it's interesting nonetheless.


In the Wikipedia article, I spotted this:

Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland and the enterochromaffin cells [...]. Genetically altered mice lacking TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure.

"Easily tired" sounds familiar for ME patients, and I've heard at least one clinician (Cheney or Hyde?) talk about ME being a state of chronic heart failure, with heart dysfunction.

 

[Bob]

There's an interesting related paper, in relation to autoimmunity and 'neuropsychiatry' in the following thread:
http://forums.phoenixrising.me/index.php?threads/autoimmune-inflammation-and-monoamines.23222

The study reviews the link between autoimmunity and neuropsychiatric disorders.
There's an interesting list of symptoms that alex3619 has posted in the thread.

 

[Dufresne]

I have hypothesized that one possible mechanism for post viral (actually many pathogens that can infect the gut wall or liver) fatigue to turn to ME is a failure of LPS detox, resulting in prolonged LPS in the blood stream. Thats an emergency signal to the immune system, it goes nuts.

I believe something like this to be central for many of us as well. Considering the following points, I think it’s difficult to downplay the potential importance of this idea.



-Dr Cheney recently stated ME/CFS is indistinguishable from mould illness and that he and Dr Shoemaker routinely trade patients. From this I conclude that something as simple as mould CAN cause all our symptoms.

-Several credible CFS/Mould patients have relieved themselves of PEM through mould avoidance. Many of Shoemaker’s patients actually get well and rid themselves of this symptom too. If PEM is the cardinal symptom in ME/CFS doesn’t it stand to reason that much of the problem is mould or something acting on the immune system in a similar way?

-Shoemaker has written that CIRS (chronic inflammatory response syndrome) -which, again, is indistinguishable from ME/CFS- can also be caused by exposure to LPS.

-Studies consistently show evidence of an increase of LPS translocation in ME/CFS.

 

[Simon]

Brief commentary - too good to be true (probably)

In some ways this study looks almost too good to be true. Lots of researchers have suspected an autoantibody link with ME/CFS but here we have one with 61.5% in a large sample of patients. And patients with 5HT autoantibodies (a-5HT) have worse symptom scores than those without, suggesting this finding is biologically as well as statistically significant.

I looked at the full text but have to admit I found it heavy-going, though I suspect I'm not alone judging by the lack of detailed comments on the paper here . Here's what I gleaned, and it makes me suspect this is indeed too good to be true:

1. An earlier large study cited by the authors found only low levels of a-5HT (9% of 81 CFS patients), suggesting these results are not definitive

2. As Marco pointed out above, these findings are not specific for ME/CFS (83% were a-5HT postive in melancholic depression according to another study from Maes et al)

3. Comparing ME/CFS/CF patients who were postive for a-5HT vs those negative, the positive a-5HT were patients were on average worse (symptoms and higher biomarker levels) than negative a-5HT patients, but the effect size between the two groups was only moderate - ie the differnces were not that big.

Here's an illustration of a moderate (medium) effect size (assuming normal distribution):

Although the abstract claims that fatigue and neurocoognitive symptoms were worse in ant-5HT positive patients, the data in Table 3 show that the differences were non-significant for fatigue, concentration, memory and insomnia. Although the flu-like malaise was significantly worse in 5-HT positive patients, the p value was only p=0.02, so if they had correcteed for muliple comparisons, which would be normal, this finding would not be significant ether. Sadness, muscle pain and autonomic symptoms were all significantly worse, as was the overall symptom score.

Some other concerns

• lots of missing data: the sample seems to have been based on those patients (117) with a-5HT data but they didn't have complete data on these for the other biomarkers eg only 70 patients for IL-10 and 91 for neopterin, with a higher proportion missing for controls.
• Controls were not individually-matched for age and sex as they were, say in the Hornig study underway. Given that there is a lot of variation in immune markers in the population anyway, this could add 'noise' to the data as age and gender often affect such results (nb the groups overall were matched on age and gender)

I don't know if the Hornig study, which is much larger than this, will be looking at the same biomarkers, though I'm sure they will looking at Interferon-alpha. Will be interesting to see if the studies agree (Hornig has done a lot of work on autoimmunity in the past).

Let's hope there will be more studies to confirm or refute the findings in this new paper - which could be very important if replicated.

 

[tatt]

. The links between LPS and other issues in ME are growing, and I want to blog on this later..

what's LPS?

 

[snowathlete]

Brief commentary - too good to be true (probably)

In some ways this study looks almost too good to be true. Lots of researchers have suspected an autoantibody link with ME/CFS but here we have one with 61.5% in a large sample of patients. And patients with 5HT autoantibodies (a-5HT) have worse symptom scores than those without, suggesting this finding is biologically as well as statistically significant.

I looked at the full text but have to admit I found it heavy-going, though I suspect I'm not alone judging by the lack of detailed comments on the paper here . Here's what I gleaned, and it makes me suspect this is indeed too good to be true:

1. An earlier large study cited by the authors found only low levels of a-5HT (9% of 81 CFS patients), suggesting these results are not definitive

2. As Marco pointed out above, these findings are not specific for ME/CFS (83% were a-5HT postive in melancholic depression according to another study from Maes et al)

3. Comparing ME/CFS/CF patients who were postive for a-5HT vs those negative, the positive a-5HT were patients were on average worse (symptoms and higher biomarker levels) than negative a-5HT patients, but the effect size between the two groups was only moderate - ie the differnces were not that big.

Here's an illustration of a moderate (medium) effect size (assuming normal distribution):

Although the abstract claims that fatigue and neurocoognitive symptoms were worse in ant-5HT positive patients, the data in Table 3 show that the differences were non-significant for fatigue, concentration, memory and insomnia. Although the flu-like malaise was significantly worse in 5-HT positive patients, the p value was only p=0.02, so if they had correcteed for muliple comparisons, which would be normal, this finding would not be significant ether. Sadness, muscle pain and autonomic symptoms were all significantly worse, as was the overall symptom score.

Some other concerns

• lots of missing data: the sample seems to have been based on those patients (117) with a-5HT data but they didn't have complete data on these for the other biomarkers eg only 70 patients for IL-10 and 91 for neopterin, with a higher proportion missing for controls.
• Controls were not individually-matched for age and sex as they were, say in the Hornig study underway. Given that there is a lot of variation in immune markers in the population anyway, this could add 'noise' to the data as age and gender often affect such results (nb the groups overall were matched on age and gender)

I don't know if the Hornig study, which is much larger than this, will be looking at the same biomarkers, though I'm sure they will looking at Interferon-alpha. Will be interesting to see if the studies agree (Hornig has done a lot of work on autoimmunity in the past).

Let's hope there will be more studies to confirm or refute the findings in this new paper - which could be very important if replicated.

Thanks Simon! That summary was super helpful...

 

[alex3619]

what's LPS?

LPS = lipopolysaccharide, a bacterial toxin produced by many bacteria including natural gut bacteria. We should have major defences against it, first in the lining of the gut wall, then in the gut immune system, and finally in the liver where it is detoxed. For it to pass into general circulation requires that all three layers of defence fail. The latest paper by Maes which is the topic of this thread does indicate that the damage could occur in the gut immune system, an issue with which I have yet to really investigate.

However, one issue that is underappreciated is that LPS is actually a family of chemicals. Different bacteria produce different forms. Nobody has investigated whether or not the issues in ME are associated with a particular type/s of LPS, and hence particular types of gut bacteria.

I hoped to blog on this later this year, but all my blogs have been put back by three months. So sometime early next year I may blog on this.

EDS and glutathione depeletion may both predispose to this problem, as will enteroviral infection, or even infections like giardia.

 

[tatt]

with missing data and other studies not showing similar results this doesn't sound too promising. However immune/ inflammatory issues seem quite likely and immunity starts in the gut. I look forward to reading the blogs.

 

[Simon]

what's LPS?

A slightly different perspective

LPS is Lipolpolysaccharide, a key component of the outer cell wall in some bacteria

LPS is also called 'endotoxin', making it sound like a toxin produced by bacteria, which isn't exactly the case. Many bacteria have a single cytoplasmic membrane, just like us, but gram-negative bacteria - which includes Salmonella, K pneumoniae, Legionella and quite a few that cause STDs - have a second, outer membrane. And that outer membrane is studded with Lipopolysaccharide, LPS:

LPS forms a protective layer, one reason why many gram-negative bacteria are resistant to antibiotics.

So why is LPS toxic? LPS is a massive marker that bacteria are on the loose and can provoke a huge immune response, which can itself harm the body. LPS is recognised by a receptor called TLR4 (Toll-like Receptor, if you really care), which is conserved in species from fruit flies to humans, a sign that this receptor is crucial to survival.

LPS is only recognised once free in the blood etc, not while part of bacteria, so it's only released when the bacterium dies (hence the name 'endotoxin', as opposed to exotoxins secreted by living bacteria).

The body must react quickly to LPS to counter the bacterial threat, but over-reaction can be very harmful too (the usaul problem with the immune system being too powerful and harming the body as well as the bug). So the body needs to remove LPS to effectively 'turn off the alarm' - hence there is a system to detoxify LPS, as Alex mentions.

However, even with detox systems, LPS is a detectable sign of infection with gram-negative bacteria, presumably the reason it was looked for in this study.

Interestingly (or not), researchers often use synthetic LPS to study the immune response separate from specific effects of any bacteria. The body (OK, usually a poor mouse's body) reacts to LPS as if there is an infection, but since there are no bacteria involved, any symptoms/chemical changes are down to the body's immune response, rather than any bacterial toxin etc. Neat (or not).

 

[alex3619]

Immune cells migrate to locations with LPS. If you have a bacterial infection in the lungs for example, many immune cells will migrate there. One of those cells is the gamma delta T cell, which has a hard coded recognition system, and different gamma delta T cells react to different substances - all hard wired by evolution. The gamma delta T cell is an immune activator, but its also an immune suppressor and important in controlling autoimmune reactions. It also initiates wound healing.

If there is a constant source of LPS in the body other than the gut, what happens to the gamma delta T cells in the gut? I don't know, but they might migrate out. If so then gut healing and suppression of autoimmune issues in the gut immune system would both be compromised.

There is a lot of detail in this, which is why I intend to write a blog. LPS as a topic keeps coming up, so I wanted a blog I could point people to. I currently expect to write this early next year.

 

[snowathlete]

Interesting to read that there are different forms of LPS. That might explain why we tolerate the LPS that some good bacteria have in our bodies...?

Also, an interesting point to add is that some viruses attach to LPS and it is thought that this helps them to evade the immune system, and be more successful in surviving and infecting cells. Polio is one such virus but there are others as well.