Jarred Younger on Neuroinflammation in ME/CFS and Fibromyalgia

[zzz]

There's an excellent article on Health Rising discussing Jarred Younger's work on neuroinflammation in ME/CFS and fibromyalgia. It's entitled The Neuroinflammation Man: Jarred Younger on Inflammation, Fibromyalgia and Chronic Fatigue Syndrome. I found it to be a fascinating discussion of the mechanisms of neuroinflammation, including some of the latest research findings, as well as possible directions for future treatments. I think that Younger makes an excellent case for how central neuroinflammation may be in ME/CFS and related disorders, and how important it is to treat it.

 

[Marky90]

There's an excellent article on Health Rising discussing Jarred Younger's work on neuroinflammation in ME/CFS and fibromyalgia. It's entitled The Neuroinflammation Man: Jarred Younger on Inflammation, Fibromyalgia and Chronic Fatigue Syndrome. I found it to be a fascinating discussion of the mechanisms of neuroinflammation, including some of the latest research findings, as well as possible directions for future treatments. I think that Younger makes an excellent case for how central neuroinflammation is in ME/CFS and related disorders, and how important it is to treat it.

I think its an interesting hypophesis, but I dont like that they completely ignore the results from Haukeland on Rituximab in the article. That would be the first thing I would ask about..

 

[Sasha]

This is particularly interesting:

Effective treatments are, of course, the ultimate goal. Studies suggest that some antibiotics and antivirals as well as LDN and herbal preparations may all have microglial inhibiting properties. But what about new drugs? Are new drugs being specifically developed yet to rein in over-active microglia?

Absolutely. Many groups are working on new microglia modulating compounds. There are dozens being tested right now. Some of those promising agents push the microglia back into their resting state, while other agents push the microglia into an alternative, neuroprotective state (called the M2 state).

Any one of those agents may be very successful in treating ME/CFS or FMS. Unfortunately, the process of developing a new pharmaceutical, testing it for safety and efficacy in animals, and progressing cautiously in humans takes many years. Also, there is no true FMS or ME/CFS animal model.

So, there is a big risk that we will miss an important drug only because animals did not respond well to it. For those reasons, it is critical that we test currently-available compounds that can be used in humans much more quickly.

I asked Younger how he was testing possible microglial inhibitors?

Our technique for testing microglia inhibitors is fairly basic. We read the scientific literature to create a prioritized list of compounds to try. The compounds with the most convincing basic science support (typically in cell cultures or in animals) will be placed at the top of our list.

Then, we give those compounds to individuals with ME/CFS or FMS in a closely-monitored clinical trial. We are going to be testing several such compounds this year.

Participating in a clinical trial is sometimes the only way to try new medications before they are available to the public (usually a few years in advance). But they are also typically more risky because we haven’t collected as much safety data. We do our best to pick only those compounds that seem to be safe.

Ron Davis has been proposing that advances in ME/CFS are going to open up understanding of other diseases. Do you feel that’s true for ME/CFS and fibromyalgia and, if so, how?

I believe that many disorders are at least partially driven by brain inflammation, so I definitely agree with Dr. Davis. Any treatment found to be effective for ME/CFS or FMS should be immediately tried in the other disorder.

The same goes for: Gulf War Illness, irritable bowel syndrome, major depressive disorder, cognitive problems after traumatic brain injury, fatigue from rheumatoid arthritis, fatigue due to cancer treatments, and dozens of other conditions.

I also believe neuroinflammation drives many symptoms of normal aging, such as increased fatigue and decrease cognitive functioning. An effective and safe anti-neuroinflammation agent may become something that almost anyone could take, similar to how aspirin is used by so many people to help control peripheral inflammation.

Read more: The Neuroinflammation Man: Jarred Younger on Inflammation, Fibromyalgia and Chronic Fatigue Syndrome http://www.cortjohnson.org/blog/201...on-fibromyalgia-and-chronic-fatigue-syndrome/

 

[Sasha]

And:

I asked him how the fibromyalgia and chronic fatigue syndrome communities could support him in his work?

Thank you for asking. Without a doubt, the biggest obstacle to successfully completing a human research study is recruiting the participants.

Every study we conduct requires people, both ill and healthy, to dedicate their time to the project. No new diagnostic techniques and no new treatments can be developed without those individuals. We are especially grateful for those participants when the disease itself makes coming to the laboratory so difficult.

We have had a great response from the community since moving to Alabama, and have a good list of individuals who are interested in participating. But as the laboratory grows, the studies will grow as well, and we will need more and more people to volunteer.

So, the best support people can give is to participate in studies if they can. We completely understand that sometimes people are just too sick to help in that way. The next best thing they can do is get the word out to as many people as they can whenever we have a new study or research finding.

As our group becomes more nationally and internationally recognized, it allows us to attract more participants, more donors, and more resources. I think it is very likely we could leverage that reputation in the future to develop a large, interdisciplinary research center specifically for these disorders, and start studies that operate across the United States to reach as many people as possible.

We are on track to make those things happen, so I am very excited to be in the position I am in.

Read more: The Neuroinflammation Man: Jarred Younger on Inflammation, Fibromyalgia and Chronic Fatigue Syndrome http://www.cortjohnson.org/blog/201...on-fibromyalgia-and-chronic-fatigue-syndrome/

 

[Sasha]

You can sign up for Jarred Younger's newsletter here: http://www.psy.uab.edu/younger/index.html

And they want online participants for this study: https://uab.co1.qualtrics.com/jfe/form/SV_0vNM8AOd9FJsnPf

I'll start a new thread on that so it gets attention.

 

[JPV]

I think its an interesting hypophesis, but I dont like that they completely ignore the results from Haukeland on Rituximab in the article.

Sounds like two different approaches to me. Younger seems to be focused on directly inhibiting microglial activity. Rituximab, if I understand it correctly, kills off unhealthy B cells which are replaced with healthy ones. The goal being to control overactive immune system activity.

 

[Sasha]

What do you reckon to this line of research, @Jonathan Edwards? Do they tie in at any point?

 

[Marky90]

It seems so JPV, but I dont find it it reasonable to stick ones head in the sand with two thirds responding to rtx.

Jonathan had a very interesting comment in another thread:

"There is a mechanism that we have been discussing amongst scientists in the UK interested in the potential role of B cells. Rituximab must be working by removing B cells, I think, since it really does nothing to anything else. If we think the Norwegian data indicate a real effect I think we have to take into account that this effect takes about 6 months to be fully apparent. That points strongly in the direction of the effect being through antibody production rather than some immediate effect of B cells through something like antigen presentation.

So how would blocking new antibody production over a six month period help if these were not autoantibodies? I think there is a genuine alternative possibility. The antibody that declines with six months of B cell depletion is antibody produced by short lived (mostly splenic?) plasma cells. This sort of antibody probably includes a relative high proportion of low affinity/broad specificity antibody - sort of rough and ready dirty antibody. If we postulate that ME in the chronic phase is due to a hypersensitivity of brain stem/autonomic circuits to very low level immune danger signals it might be that what generates symptoms are the normally trivial levels of cytokine or other signal that occur as part of normal daily clearance of toxic material and low grade microbes. A good part of those signals may be triggered by interactions with 'rough and ready' antibody. So if the immune system is 'flushed out' of such antibody without the ability to top it up then symptoms may improve.

We considered this idea because we needed to to think about how one might see improvement with rituximab and yet find no apparent 'abnormality' in B cells or antibody levels or specificities."

Now that hypophesis would be so interesting to pursue.. Or at least hear Youngers` thoughts on

 

[Vojta]

This excellent article also makes sense in context of neuroborreliosis. As some ME/CFS specialists suggest these days that many patients could have seronegative lyme.

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000659
"We report findings that implicate microglia, a macrophage cell type in the CNS, as the key responders to infection with B. burgdorferi. We also present evidence indicating that this organism is not directly toxic to neurons; rather, a bystander effect is generated whereby the inflammatory surroundings created by microglia in response to B. burgdorferi may themselves be toxic to neuronal cells."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847353/
"...apoptotic death of neurons and oligodendrocytes following spirochete treatment, suggesting that in addition to direct damage by the bacteria, the glial response to B. burgdorferi likely also contributes to cell death."
"..evidences suggest that inappropriate immune activation may be playing a role during chronic disease. Therefore, the dampening of microglial pro-inflammatory cascades to favor anti-inflammatory pathways following pathogen eradication may benefit patient outcome from Lyme neuroborreliosis, although this conjecture remains speculative at the present time."

 

[SilverbladeTE]

Also shows that M.E. *IS* a reasonable term for this illness and should never have been changed for political concerns.
Nomenclature of disease is often little to do with the mechanics of the illness anyway, based on old terms etc.

 

[Scarecrow]

It seems so JPV, but I dont find it it reasonable to stick ones head in the sand with two thirds responding to rtx.

Just thinking aloud here. Bear with me, it may be nonsense.

Rituximab as a potential therapy for ME came about by chance observation. As far as I know it was because a couple of patients reported an improvement in their ME symptoms while receiving treatment for lymphoma. Fluge & Mella were intrigued and trialled it on a small number of ME patients. Who knows what they were thinking in terms of mechanism of action at this point. Perhaps it was little more than simple curiosity. Could it possibly work or were the patient reports of improvement simply coincident with the lymphoma treatment? Obviously, they now have theories about what could be going on. Significantly, they're not limiting potential therapies to rituximab.

If the theory of over-sensitised microglia in ME is correct how would you go about joining up the dots between microglia and rituximab? Cytokines, perhaps? Surprisingly (to me at any rate) rituximab has been used in HIV patients with MCD, which is a lymphoproliferative disorder "with marked systemic symptoms attributed to cytokine disarray".

 

[Scarecrow]

oops! posted too soon. Sorry.

 

[Scarecrow]

I don't think that there is a suggestion that MCD is an autoimmune disease. Rituximab therapy decreased the levels of certain cytokines.

Markedly elevated cytokine levels were observed before rituximab therapy, and a reduction in baseline values with rituximab therapy was observed for IL-5, IL-6 and IL-10.

The rituximab was given in four doses at weekly intervals. The cytokine reduction happens relatively quickly but it's long lasting. Here's the link to the original MCD rituximab study.
http://www.ncbi.nlm.nih.gov/pubmed/19224759

We already know that the average response time to rituximab in ME responders is very nearly six months. Does this mean that it can't be anything to do with lowered cytokine production?

Here's where I start speculating wildly. In the absence of a stimulating factor (rather than an agent that actively switches the microglia into an alternative state), how long would it take for the sensitised microglia to resume their resting state? Could we be talking about months?

Edited to add that I don't think it's necessary for Younger to be thinking too deeply about rituximab.

If the sensitised microglia theory is correct (for some) and rituximab is effective (for some), it will either be because they are connected in some way or because of subsets.

 

[Marky90]

I don't think that there is a suggestion that MCD is an autoimmune disease. Rituximab therapy decreased the levels of certain cytokines.

The rituximab was given in four doses at weekly intervals. The cytokine reduction happens relatively quickly but it's long lasting. Here's the link to the original MCD rituximab study.
http://www.ncbi.nlm.nih.gov/pubmed/19224759

We already know that the average response time to rituximab in ME responders is very nearly six months. Does this mean that it can't be anything to do with lowered cytokine production?

Here's where I start speculating wildly. In the absence of a stimulating factor (rather than an agent that actively switches the microglia into an alternative state), how long would it take for the sensitised microglia to resume their resting state? Could we be talking about months?

I dont have the answers Scarecrow, But I have a huge gut feeling it*s either antiautobodies attacking.. Something. Or its something to do with how the microglia (or alike?)responds to antibodies. Thats my conclusion from reading the literature on this almost everyday (and of course not my own hypophesises), for a prolonged period of time. Hopefully none of those two alternatives are dead wrong

 

[Scarecrow]

I dont have the answers Scarecrow,

Yeah we're in the same boat there. For certain.

I can't help thinking about the rapid shifts in symptoms that so many of us can relate to. A rapid worsening doesn't perplex me too much but if autoantibodies were responsible, why would some people experience rapid improvements, which can sometimes manifest in around 15 minutes? Just beyond weird.

 

[Marky90]

Yeah we're in the same boat there. For certain.

I can't help thinking about the rapid shifts in symptoms that so many of us can relate to. A rapid worsening doesn't perplex me too much but if autoantibodies were responsible, why would some people experience rapid improvements, which can sometimes manifest in around 15 minutes? Just beyond weird.

I think such rapid improvements are rare? Personally I get huge improvement from alcohol, which points towards issues with vasodilation (but then again it could be something else). I guess we are all differently affected by this disease. Which kinda makes sense when you take into consideration that we got different immune systems..

 

[Jonathan Edwards]

I think its an interesting hypophesis, but I dont like that they completely ignore the results from Haukeland on Rituximab in the article. That would be the first thing I would ask about..

Like the Chinese, US researchers hate anything not invented in their country. Science is a bit like a baseball match for them it sometimes seems. One gets used to it.

 

[Jonathan Edwards]

What do you reckon to this line of research, @Jonathan Edwards? Do they tie in at any point?

Microglial activation is one of the areas I think is most worthy of study. I am all for it.

I hate the term neuroinflammation though. It is a trendy buzzword that confuses everyone. This is not really inflammation in any helpful sense. It is a new type of problem that deserves its proper name - which is:

microglial activation.

 

[Jonathan Edwards]

To be fair to Younger, I suspect he was not asked to talk about wider options. And a B cell/antibody mechamism would tie in to microglial activation very easily. Presumably autoantibodies or maybe not-so-auto-but-bad-antibodies would activate either microglia directly or via interactions with antibody Fc receptors on cells in the peripheral immune system, with nerve signals sent on to annoy the microglia. There are any number of ways of doing that. One idea I was intrigued by was that it was through the Fc receptor Fc R1, which is on microglia and which might not trigger typical inflammation but might lead to gamma interferon production for instance.

Thinking about the other current thread on rituximab it might well be useful to give inhibitors of microglial activation for a quick response and then follow up with rituximab or a newer better B cell drug to deal with longer term remission.

 

[Scarecrow]

Thinking about the other current thread on rituximab it might well be useful to give inhibitors of microglial activation for a quick response and then follow up with rituximab or a newer better B cell drug to deal with longer term remission.

If microglia are implicated and effective inhibitors can be found or developed, why not keep taking them?