• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Jarred Younger's Take On The Rituximab Trials

Jonathan Edwards

"Gibberish"
Messages
5,256

Hmm.

I think we know what the disease is when B cells get into the brain and cause inflammation. It is called multiple sclerosis and has pretty little similarity in terms of pathology to ME. B cells are not inflammatory cells until they turn into plasma cells, as they do in MS and produce oligoclonal antibodies. When they do get into brain they tend to cause clear cut damage with demyelination. And as someone pointed out, the time scale does not fit for Younger's theory. My impression is that Younger is dipping his toe into a complex field that he is not very familiar with.

Interesting to see the group led by Steve Hauser talking of B cells as drivers of MS (@Never Give Up). When I talked about this at a meeting in California some years ago he and his friends poo-pooed the idea that this was B cell driven - they were stuck with T cells. But they will learn!! He may yet to learn that the B cells are working through the very antibodies they have been studying, or maybe he has even worked that out already.
 

msf

Senior Member
Messages
3,650
HI Scarecrow - basically that LPS from the 'leaky gut' is driving, or contributing to the illness. It would seem to do this throw the leptin mechanism that Younger describes in his video.
 

Hip

Senior Member
Messages
17,824
This is a little off topic, but from my own experience, and my understanding of the work of Maes and De Meirleir, LPS is going to be important, but Younger sort of passes over it without making any suggestions about how it may be involved in the process.

In the video posted earlier in this thread, Jarred Younger briefly mentions LPS in the context of microglial priming. Microglia priming is a sensitization of microglia, and amplification of microglial inflammatory responses.

Younger also points out in this video that there are many other environmental triggers of microglial activation and priming, including for example diesel particles in the air from oil fires.

Some highlights of the video:
Timecode 17:30Jarred Younger measured the day to day fluctuations in ME/CFS symptoms, and by taking blood samples on the same days, he looked for what changes in the blood correlated to these daily symptom variations. It turns out the only correlation found was between blood leptin levels and fatigue.


Timecode 26:45leptin sensitizes microglia. Leptin does not really do anything to microglia cells by itself, but when microglia cells are exposed to inflammatory triggers like LPS (lipopolysaccharide), the inflammatory response from microglia is much stronger if they have been exposed to higher levels of leptin, and what's more, microglia are also triggered into their inflammatory state much more easily after exposure to leptin.

So leptin is both a sensitizer and amplifier of the inflammatory response from microglia (this sensitization of microglia and amplification of microglial response is called microglial priming).


Timecode 28:20overview of Jarred Younger's working hypothesis of ME/CFS. His working hypothesis is:

• Some factor initially causes microglia hyper-reactivity (microglial priming) — and there are many environmental or infectious factors that can do this.
• Then once these microglia have become hyper-sensitive, they can over-react to factors present in the body (presumably things like chronic viral infections).


Timecode 30:10 — the strong relationship in 6 out of 10 ME/CFS patients between the day to day fluctuations in fatigue levels, and the day to day variations in leptin levels (the lower the leptin, the lower the fatigue).

Interestingly, a few patients actually showed an inverse relationship between fatigue levels and leptin: for them, the higher the leptin, the lower than fatigue. Jarred Younger says he does not yet have a hypothesis that might explain these inverse relationship cases.


Timecode 49:40 — some speculation by Younger on what may have caused the various ME/CFS epidemics. Younger points out that things like diesel particles in the air (arising from oil fires) can act as an microglia reactivity sensitizers (microglial primers), and this has been shown in rodent models. Younger says that there are many environmental factors that can cause such microglial sensitization, and speculates that the presence of such microglial sensitization factors, in combination with a viral outbreak, may have caused these ME/CFS epidemic outbreaks.


The above highlights originally from this post.
 

JPV

ɹǝqɯǝɯ ɹoıuǝs
Messages
858
This is a little off topic, but from my own experience, and my understanding of the work of Maes and De Meirleir, LPS is going to be important, but Younger sort of passes over it without making any suggestions about how it may be involved in the process.
At about 26:40, in the video that I posted earlier, he explains how when Leptin comes in contact with Microglia cells they don't really release much TNF-alpha. He claims that it takes a combination of both Leptin and LPS to cause the Microglia to start releasing significant amounts of TNF-alpha.

He doesn't really explain the origins of the LPS very much but I'm assuming it comes from inordinate amounts of gram negative bacteria that may be present in the gut...

rRk0mBf.png

Gksnd3D.png
 

Hip

Senior Member
Messages
17,824
He claims that it takes a combination of both Leptin and LPS to cause the Microglia to start releasing significant amounts of TNF-alpha.

He doesn't really explain the origins of the LPS very much but I'm assuming it comes from inordinate amounts of gram negative bacteria that may be present in the gut...

In these experiments on microglial cells, the LPS is administered by the researchers, as LPS is a well-known trigger of microglial activation, and thus often used in such experiments on microglia (interferon gamma is another well-known trigger of microglial activation).

The experimental use of LPS does not imply (nor deny) that LPS may be involved in ME/CFS etiology.



To understand Younger's work, you have to grasp the concept of microglial priming.

An analogy to help explain microglial priming might be the following:

Imagine an individual who has been conned by con artists.

Because of their past experience, that individual may now have become hyper-sensitive to any new people he deals with, becoming much quicker to pick up on anything suspicious in people he meets; and whenever that individual senses even the slightest hint that something may be amiss in a new person he is dealing with, that individual will react very strongly in order to protect himself from the possibility of being conned again.

That conned individual will find it hard to forget being conned in the past, and so will henceforth much more vigilant than normal.

Likewise with microglia: when microglia first encounter certain significant inflammatory conditions, they henceforth become much more vigilant than normal: they become hyper-sensitive to any further inflammatory triggers, and react more strongly than normal when they meet new inflammatory circumstances.


In the context of ME/CFS, this means that if we had encountered an event earlier in our lives that primed our microglia, then later on, that may cause a far stronger inflammatory response from our microglia when we catch say an EBV or enterovirus infection. Because of the priming, we over-react to the virus, and this leads to developing ME/CFS, at least according to this microglial priming theory of ME/CFS.


There is some more info on microglial priming in this post, and also a PR article on priming here.
 
Last edited:

Never Give Up

Collecting improvements, until there's a cure.
Messages
971
Dr. Younger's response to a question about whether there is any evidence that B-cells ever get into the brain and that once there, cause inflammation.

Neuroinflammation, Pain, and Fatigue Laboratory at UAB
Nice paper recommendation, Lucy. There are a good collection of papers (mostly in animal subjects) showing that B-cells and T-cells can reach the brain during states of neuroinflammation. In human studies, they are typically measured from the spinal cord fluid, which is not quite the brain, but generally considered to be close enough. Jarred Younger
 
Last edited by a moderator:

nandixon

Senior Member
Messages
1,092
I think we know what the disease is when B cells get into the brain and cause inflammation. It is called multiple sclerosis and has pretty little similarity in terms of pathology to ME. B cells are not inflammatory cells until they turn into plasma cells, as they do in MS and produce oligoclonal antibodies. When they do get into brain they tend to cause clear cut damage with demyelination.
I don't think it's necessary for B cells to ultimately result in the production of autoantibodies for them to potentially be problematic. See, e.g.:

Cytokine-producing B lymphocytes – key regulators of immunity

So with respect to their being troublemakers in regard to the priming or activating of microglia, the B cells would only need to be secreting types and amounts of cytokines (or other peptides or chemicals) that sensitize the microglia.

And as someone pointed out, the time scale does not fit for Younger's theory.
My understanding, from looking into this last year when we were briefly discussing essentially the same basic concept Dr. Younger is proposing in his hypothesis, is that activated microglia potentially have a very similar lifespan, i.e., several months, to that of the "short-lived" plasma cells that would be producing any presumed autoantibodies.

So when the B cells are depleted by rituximab, approximately the same amount of time might pass whether one is waiting for bad microglia to deactivate as in Younger's theory, or for bad plasma cells to die off as in the autoimmunity theory.

(Here's where the earlier discussion occurred if anyone is interested:
http://forums.phoenixrising.me/inde...rence-1-2-sept-2014.32344/page-22#post-540184)
 
Last edited:

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
Dr. Younger is proposing in his hypothesis, is that activated microglia potentially have a very similar lifespan, i.e., several months, to that of the "short-lived" plasma cells that would be producing any presumed autoantibodies.

Does that assumption have any foundation?
 

nandixon

Senior Member
Messages
1,092
Does that assumption have any foundation?
I think there may have been a translation problem there. :) I wasn't saying that Dr. Younger was proposing that as part of his hypothesis.

Rather, activated microglia having a lifespan of several months was what I'd found in the research I did last year. When I have a chance I'll see if I can re-find some references, unless you or someone else beats me to it.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
I think there may have been a translation problem there. :) I wasn't saying that Dr. Younger was proposing that as part of his hypothesis.

Rather, activated microglia having a lifespan of several months was what I'd found in the research I did last year. When I have a chance I'll see if I can re-find some references, unless you or someone else beats me to it.

Oh, thats pretty exiting! Didnt find anything myself, so you`ll probably beat me to it :)
 

nandixon

Senior Member
Messages
1,092
@Marky90

Now that I revisit this I see that I was probably thinking about the potential lifespan of possible associated T (memory) cells that might be causing the microglia to remain activated under the theory I mentioned in this old post (and the study I cited there):

http://forums.phoenixrising.me/inde...rence-1-2-sept-2014.32344/page-22#post-540225

(And I probably should have said "persistence" rather than "lifespan" in association with activated microglia.)

I'll still try to look into this some more to see what kind of persistence in activation might be expected under other scenarios.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
LPS is what is known as a super antigen. It makes the immune system go nuts. I have no doubt that if the blood supply can carry it into the brain it might have effects way beyond just microglial activation. Does anyone know if LPS has been found in spinal fluid?

One of the things we face in ME and CFS investigation is that we have oodles of symptoms and biochemical findings. The possible mechanisms overlap in big spaghetti tangles. So the theory of what causes what is messy. What tends to happen is that most focus on one bit of the tangle and postulate some factor is causing that.

Correlation does not prove causation, though ti can justify an hypothesis for investigation. Systems biology may help us find the key players in those spaghetti tangles, and focus on them. Theoretical speculation can give us good hypotheses, but we still need good investigational science to test those hypotheses.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I don't think it's necessary for B cells to ultimately result in the production of autoantibodies for them to potentially be problematic. See, e.g.:

Cytokine-producing B lymphocytes – key regulators of immunity

So with respect to their being troublemakers in regard to the priming or activating of microglia, the B cells would only need to be secreting types and amounts of cytokines (or other peptides or chemicals) that sensitize the microglia.

To be honest I think that paper is rubbish - written by someone who has not been involved in B cell depletion in autoimmunity as far as I know. The key argument is based on a paper by Inaki Sanz, Jen Anolik and John Looney, who I worked in parallel with in the early days of rituximab for RA and SLE - which does not actually quite say what is quoted. Where there are relevant antibodies they go down in very good correlation with clinical improvement.

The trouble is that everybody wants to tell this story of B cells doing more than antibody because it was news - in about 1994!! Suddenly we were told that B cells presented antigen and made soluble factors. Unfortunately the papers were written by people who were still at school when these things were discovered in the 1970s and early 80s. B cells make absolutely minute amounts of cytokine in comparison to true inflammatory cells like macrophages and will only do so if they are in the right microenvironment. I know this stuff is flavour of the month (a rather long month since 1994) but immunologists are like sheep - they follow whatever they are told.

The bottom line is that there is essentially no evidence for B cells doing anything important except make antibody in human autoimmunity.

I agree that the time lag could be due to die off of activated microglia but I really don;t believe there are B cells in the brain in ME. For there to be B cells surviving in brain you would need tissue disturbance occupying an area of a minimum of 500microns cubed - to get a microenvironment going. That is almost certain to produce neurological signs of the sort seen in MS. Nobody has found isolated individual B cells in brains - B cells are very unhappy on their own in tissues. We now know from the channelopathies that antibody gets into brain. We have no evidence for B cells getting into brain in the sort of way that might tickle up microglia without producing neurological signs. I don't buy it.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
My understanding, from looking into this last year when we were briefly discussing essentially the same basic concept Dr. Younger is proposing in his hypothesis, is that activated microglia potentially have a very similar lifespan, i.e., several months
Rather, activated microglia having a lifespan of several months was what I'd found in the research I did last year. When I have a chance I'll see if I can re-find some references, unless you or someone else beats me to it.
Now that I revisit this I see that I was probably thinking about the potential lifespan of possible associated T (memory) cells that might be causing the microglia to remain activated...
I know very little about this issue, but I'm pretty sure that Jarred Younger said that microglia tend to remain activated for a period of months (or weeks to months?) in one of his videos. (But my memory is unreliable.) I've not yet read anything about this in any published research, as far as I remember.
 
Last edited:

Jonathan Edwards

"Gibberish"
Messages
5,256
I know very little about this issue, but I'm pretty sure that Jarred Younger said that microglia terms to remain activated for a period of months (or weeks to months?) in one of his videos. (But my memory is unreliable.) I've not yet read anything about this in any published research, as far as I remember.

My memory of when we talked about this before was that it seemed that microglia could increase in number and become activated and these changes might last for anything from weeks to years. I agree that the time lag in the apparent rituximab response could fit this but I think my feeling was that since it fitted very neatly into the short lived plasma cell time scale we see in other autoimmune conditions and for microglia we might expect it to be much more spread out or just as likely to be something else then the plasma cell hypothesis looks a bit more of a betting favourite. having said that I think the Norwegians are now finding people getting better even later - which again would fit either since there are some RA patients who take over a year to get full response.

I agree there are lots of possibilities. I just tend to go for the one the seems to have panned out right before.
 

Hip

Senior Member
Messages
17,824
LPS is what is known as a super antigen. It makes the immune system go nuts. I have no doubt that if the blood supply can carry it into the brain it might have effects way beyond just microglial activation.

Michael Maes published a couple of papers on the translocation of LPS through the gut wall in ME/CFS patients. In his 2007 paper here, he details a young ME/CFS patient with IgM and IgA antibodies against LPS, and details the patient's full remission after an antioxidant protocol and "leaky gut diet".

In this later 2008 paper, Maes studied 41 ME/CFS patients who he put on "natural anti-inflammatory and anti-oxidative substances, such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet" for a period of 10 to 14 months. Up to 24 patients showed a significant clinical improvement or remission after this protocol, along with attenuation of their IgA and IgM responses to LPS.

Maes also published this 2009 review of the evidence for increased LPS translocation through a leaky gut (weakened tight junctions).



One could interpret these results as the anti-inflammatory and anti-oxidative supplements reducing intestinal permeability and thus reducing the translocation of LPS through the gut wall, leading to less inflammation in the body, brain and microglia.

However, another explanatory pathway (which may co-exist with the first) might be that the supplements lowered intestinal inflammation, which in turn reduced the sickness behavior response in the brain, a response which triggered when the vagus nerve detects inflammation in the gut.
 
Last edited:

Bob

Senior Member
Messages
16,455
Location
England (south coast)
My memory of when we talked about this before was that it seemed that microglia could increase in number and become activated and these changes might last for anything from weeks to years. I agree that the time lag in the apparent rituximab response could fit this but I think my feeling was that since it fitted very neatly into the short lived plasma cell time scale we see in other autoimmune conditions and for microglia we might expect it to be much more spread out or just as likely to be something else then the plasma cell hypothesis looks a bit more of a betting favourite. having said that I think the Norwegians are now finding people getting better even later - which again would fit either since there are some RA patients who take over a year to get full response.

I agree there are lots of possibilities. I just tend to go for the one the seems to have panned out right before.
The clinical response to rituximab seems to fit the autoimmunity model perfectly. But it doesn't harm to continue to explore hypothetical possibilities. It could be the case, of course, that both autoimmunity and activated microglia play a role in the illness. But in such a scenario I would imagine that the autoimmunity is upstream of the activated microglia, such that treating the autoimmunity would in turn reduce the amount activated microglia.
 
Last edited:

nandixon

Senior Member
Messages
1,092
Something else interesting in the video @JPV posted earlier in this thread.

About midway (39:21 mark) into the presentation, Dr. Younger shows a slide with a list of drugs he said could potentially be used in human trials to calm activated microglia (as opposed to addressing leptin directly):

Naltrexone
Minocycline
Ibudilast
Dextromethorphan
Rifampin
Propentofylline
Ceftriaxone
Glatiramer acetate

A number of those (bolded) are also antibiotics that Dr. Kenny de Meirleir (KDM) uses in his treatment of chronic Lyme and related. Interesting overlap there.