ME/CFS as a hyper-regulated immune system driven by an interplay between regulatory T cells & chronic human herpesvirus infections (2019) Nacul et al.

Do you mean Q fever?

 

Is Q fever linked to bacterial from goats (when they are giving birth)?

 

Yes

 

Thanks. Presentation was by Ruud Raijmakers

 

OK working my way through this, a few things worth mentioning to help other people get into it.

B cells are from Bone and T cells are from Thymus. Rituximab targets B cells and cannot treat T cell disease unless it causes B cell disease when it can kill the B cells not the T cells.

T cells show CD25 receptor which means they are responding to IL2 which is involved with the TH1/2 differentiation pathway. This is the pathway which Dr Paul Cheney and others noticed was TH2 shifted in ME CFIDS.

T regs are T cells which produce FOXP3 to regulate T eff-ector clones by a process involving conjugation with T cognate cells. Together these cells work out which clones of T eff are overreacting to self antigens and kill these clones to prevent autoimmunity.

Its a bit like Goldilocks. The model assumes T eff clones which are overreacting autoimmune responders and clones which are not reacting to any antigens at all will be killed off by T regs, and clones which are just right, reacting to mid frequency peripheral antigens, will be preserved and will proliferate to combat pathogens.

The model considers that HHVs can produce antigens which mimic human self antigens and so can trigger the T regs to respond as though it is an autoimmune antigen and kill the T eff clones which could fight the virus, thus leading to chronic infection stalemate, or, where the T effs which match the mimic antigens are not killed the immune response would cause autoimmune cross reactions.

They consider a range of mathematically described hypothetical scenarios for different human herpes viruses in their target tissues including the scenario of both chronic virus and incomplete T eff suppression leading to autoimmune reactions, inflammation and fatigue.

I think this is very interesting, ticks a lot of boxes for me and has the basis of an hypothesis worth testing regarding the role of T cells and HHVs in ME CFIDS.

But experiments will only work if cohorts are properly selected. If you mix Lymes in with HHV hosts you will get statistical gobbeldygook.

 

The problem for me, @boolybooly, is that having worked on autoimmunity all my life I don't see T effector cells as being the problem and I don't see molecular mimicry as in any way plausible. I also don't think Th1/TH2 balance exists or that Tregs have much to do with autoimmunity. I realise that there are a lot of immunologists out there wedded to these mantras but I never found any evidence to support them. They are all based on models in mice that are largely self-fulfilling.

 

I am a bit slow on the uptake sometimes but I have just realised this paper has a reference to the 2015 systematic review of cytokine responses authored by PD White et al (ref 18), as well as the 2017 paper by Montoya et al (ref 19) as linked below.

"Cytokine signature associated with disease severity in chronic fatigue syndrome patients". Montoya et al.
https://www.pnas.org/content/114/34/E7150

Both of which identified raised transforming growth factor-beta (TGF-β) to be associated with ME/CFS, which seems to have been the basis for this approach.

Judging from the wiki, knowledge about TGF-β is incomplete but one of the things which is mentioned ...

https://en.wikipedia.org/wiki/Transforming_growth_factor_beta#T_lymphocytes

Which is what this paper is all about. So it all seems to stem from the raised TGF-β observations. They appear to be following the rabbit hole as it were, to see where it leads.

I do take your opinion into consideration very seriously @Jonathan Edwards but from my own experiences I find there is something which needs explaining wrt raised allergies combined with recurrent virus on ME onset and the ideas of Dr Paul Cheney about TH2 shift and those concerning mimicry in this paper do at least address this kind of observation, which precious few other papers do so I think there might be something to this direction of travel, even if the details might need to be worked out very carefully.

Mimicry is a tricky one. Its very hard to prove if you consider cross-reaction does not prove mimicry. But speaking as a zoologist, given the wonderful examples of macroscopic mimicry in the animal and plant kingdoms I find it a credible idea because of the way evolution evidently does work through natural selection to produce mimicry for visual and other senses due to the interaction of organisms, so I dont see why the same principles of natural selection would not apply at a microscopic level due to the interactions of immune cells and pathogens. So I see it as credible but not easy to prove definitively, which I agree must be done before it would be valid to consider interventions based on the idea.

 

Cort just published a [SimmaronResearch] article on this work and author Nuno Sepúlveda.

I'm not sure if it clarifies anything discussed above. I'm wondering if Prusty's recent HHV-6 work precipitated Cort's posting at all - it is mentioned.

 

The link to the Blog has changed. It is now
https://www.simmaronresearch.com/bl...igue-syndrome-herpesviruses-regulatory-t-cell

In the blog Nuno Sepúlveda (Assistant Professor at LSHTM/Cure ME) is quoted as following up on the paper of this thread with more research. Anyone heard if this work is in fact continuing?

 

Since 80% of adults are infected with HHV-6, if this theory were correct, wouldn't there be a lot more ME seen?

In my case, I was infected with HHV-6 in 1988 and started having symptoms in 1996. Quite a lag time there.

 

There could be something similar to varicella and how it manifests as zona in some adults. Everyone is infected with varicella but most people never develop zona (shingles). An opportunistic reactivation, plausibly caused by another infection that simply opens the door for a pathogen that has already crossed inside defenses but cannot succeed without the immune system being weakened by an acute infection.

 

Aging or an incompetent immune system are the primary reactivators the latent chicken pox virus (varicella). One-third of people in the US develop shingles (per CDC Shingles | Surveillance, Trends, Deaths | Herpes Zoster | CDC)

This is quite a high percentage (only 10-18% of those 33% go on to have post herpetic neuralgia--the painful form of herpes zoster).

The varicella (chicken pox) vaccine has been available since 1995 and if vaccinated, you have a 78% less risk of developing herpes zoster later in life.

Increasing rate of children and younger people are getting herpes zoster (shingles), most probably due to the general lack of vaccinations for chicken pox, most likely, though I haven't studied the topic.

I don't know how much research has been done about the aging immune system or how another infectious process activates the varicella virus or HHV-6, in an aging or immunocompromised person.

Thanks for bringing this up, @rvallee. Another reason to take some immune system courses or buy a book (that should wear my brain out in a hurry).