3 main viruses linked to ME — enterovirus, EBV & HHV-6 — all infect B-cells: autoimmune import?

[Hip]

The three viruses that are most closely associated with ME/CFS are enterovirus (the coxsackievirus B and echovirus species), Epstein-Barr virus and HHV-6.

Now these three viruses all share a particular common characteristic: they all appear to be able to infect B-cells (B-lymphocytes).

EBV can persistently infect memory B-cells (ref: here); HHV-6 can persistently infect B-cells — HHV-6 was originally called human B-lymphotropic virus on account of its affinity for B-lymphocytes (ref: here); and in a mouse model, coxsackievirus B3 can infect B-cells in the spleen (ref: here) (and non-cytolytic forms of coxsackievirus B may conceivably be able to create a persistent infection in such B-cells; non-cytolytic enteroviruses can create persistent infections in rapidly-dividing cell types).

Could this characteristic of infecting B-cells explain why these 3 viruses are all significantly linked to ME/CFS, and are considered likely causes of ME/CFS?

In terms of how a B-cell infection could trigger ME/CFS, possibly a persistent viral infection of B-cells may create the conditions that give rise to autoimmunity, and thereby to ME/CFS. This paper hypothesizes that autoimmune diseases can be caused by infection of autoreactive B-cells with EBV.



To further support this idea, note that hepatitis C virus (HCV) also appears to infect B-cells (ref: here). Now chronic HCV infection can cause symptoms very similar to those of ME/CFS, so this again suggests that a persistent B-cell infection might create conditions that give rise to autoimmunity, and then to the ME/CFS-like symptoms of chronic hepatitis C.



I don't know enough about autoimmunity to comment any further; but I noticed that the 3 main viruses linked to ME/CFS (as well as HCV) all are able to infect B-cells, so thought this might be of some significance from the perspective of ME/CFS being a possible autoimmune disease.

Assuming ME/CFS is autoimmune, and given that we know ME/CFS is often triggered by viral infections, we clearly need to consider possible mechanisms by which these viruses might set the scene for instigating autoimmunity. I am suggesting that B-cell infection might be a mechanism worth looking into.

An idea of how a chronic viral B-cell infection might trigger autoimmunity is explained in this post (basically, viral dsRNA can activate TLR7 in B-cells, which increases T-bet, which in turn increases the risk of autoimmunity in a mice study).

 

[kangaSue]

I wonder if that plays into impaired vitamin D pathways then?

http://onlinelibrary.wiley.com/doi/10.1111/imm.12572/full
[Vitamin D is associated with many immune-mediated disorders. In multiple sclerosis (MS) a poor vitamin D status is a major environmental factor associated with disease incidence and severity. The inflammation in MS is primarily T-cell-mediated, but increasing evidence points to an important role for B cells. This has paved the way for investigating vitamin D effects on B cells. In this review we elaborate on vitamin D interactions with antibody production, T-cell-stimulating capacity and regulatory B cells. Although in vitro plasma cell generation and expression of co-stimulatory molecules are inhibited and the function of regulatory B cells is promoted, this is not supported by in vivo data. We speculate that differences might be explained by the B-cell–Epstein–Barr virus interaction in MS, the exquisite role of germinal centres in B-cell biology, and/or in vivo interactions with other hormones and vitamins that interfere with the vitamin D pathways. Further research is warranted to illuminate this tube-versus-body paradox.]

 

[Gingergrrl]

I don't know enough about autoimmune to comment any further; but I noticed that the 3 main viruses linked to ME/CFS (as well as HCV) all are able to infect B-cells, so thought this might be of some significance from the perspective of ME/CFS being a possible autoimmune disease.

@Hip I don't know anything about anything LOL but these are my thoughts as well for at least one of the sub-groups of people. In your opinion, if someone had EBV as one of their main triggers and now presents with significant autoimmune abnormalities, would they be the best candidate for RTX? I know of course, you are not a doctor, but your level of research is very high and am curious what you think?

I wonder if that plays into impaired vitamin D pathways then?

I also have impaired Vitamin D pathways and cannot maintain above an "8" without significant supplementation (however this might also relate)?

 

[kangaSue]

I also have impaired Vitamin D pathways and cannot maintain above an "8" without significant supplementation (however this might also relate)?

My vitamin D is borderline deficient too, can't recall the number offhand but I don't tolerate vit Dsupplements.

 

[Gingergrrl]

My vitamin D is borderline deficient too, can't recall the number offhand but I don't tolerate vit Dsupplements.

When I supplement normal doses, I can reach "30" but I need pretty high dose to reach "60" or higher. I know we've talked about this before so will not go off-track but am curious what @Hip thinks re: the connection he mentioned and not being able to maintain Vit D levels.

The brand I tolerate is pure Vit D in olive oil base and no other ingredients or fillers in case you might tolerate it? If so, am happy to send you the info.

 

[Woolie]

@Hip, that was pretty much my working theory for ages, but now I'm not so sure. This is a repeat of stuff I said not long ago, but the things that made me doubt the B-cell infection hypothesis were:

* The absence of MECFS symptoms in HIV+ people, despite proliferation of herpes viruses. They even get cancers that are directly associated with herpes viruses, like karposy's sarcoma. But even so, its not till the very late stages that HIV+ people feel really fatigued and sick, well after the herpes proliferation has begun to happen. They don't have the feeling ill part - which suggests to me there's something more to MECFS.

* The short lived effects of rituximab on MECFS symptoms. If the problem were viral load alone, removal of a good portion of the infected cells should alleviate the problem for good. You'd have no greater viral load than any normal healthy person (who almost all harbour latent herpes viruses). But it turns out rtx only gives temporary relief; the symptoms soon return. You might say "well, that's because there were still enough infected cells to restart the infection". But then normal people carry some herpes infected cells too, why doesn't it take root in them? Again, the answer seems to be there is something different going on with us, that can't be explained by viral load alone.

* The mutliple triggers for MECFS. The Dubbo studies showed a good proportion of people with certain non-herpes infections end up with MECFS too. Ross River virus and Q fever have nothing to do with herpes, yet they can give rise to a chronic condition that looks identical to the ones seen following an acute EBV infection. Okay, so maybe you could say that the initial infection provides the opportunity for the herpes virus to reproduce, by stimulating replication of the infected B cells. But it could easily be something more generic - stimulating the immune system in some way.

Maybe herpes has a role to play in creating the conditions that make our immune systems spiral out of control. But perhaps its just too simple to say MECFS is just a problem with high levels of latent herpes infection.

 

[Gingergrrl]

@Hip, that was pretty much my working theory for ages, but now I'm not so sure. This is a repeat of stuff I said not long ago, but the things that made me doubt the B-cell infection hypothesis were:

I lack the science to back up any of my ideas but what if what starts out as immune deficiency and uncontrollable herpes viruses later morphs into an autoimmune disorder and the RTX is killing (reducing?) the auto-antibodies so the person gets temporary relief but then when the B-cells grow back, the auto-antibodies also grow back so that is why it is not permanent (and nothing to do with the herpes viruses in us vs. someone with HIV?)

 

[Woolie]

I lack the science to back up any of my ideas but what if what starts out as immune deficiency and uncontrollable herpes viruses later morphs into an autoimmune disorder

I lack the science too, @Gingergrrl, but your suggestion makes sense. And maybe what we're both saying is actually quite close to what @Hip was saying too.

 

[A.B.]

Dr Fluge wrote

The long lag time from rapid initial B-cell depletion to start of the clinical response (2-8 months) is why we do not think elimination of EBV or CMV is the principle mechanism for symptom relief in our patients. In my work as a lymphoma oncologist, I have treated a few patients with chronic EBV infection, with moderate lymphadenopathy, night sweats and general symptoms for several years, and with no clear clinical benefit from valganciclovir.

In one patient, the B-cells in bone marrow and in lymph nodes were packed with EBV and she had a high EBV titer in her peripheral blood. When given rituximab, her symptoms waned in a few days after start of treatment – very different from what we see when treating ME/CFS patients.

http://simmaronresearch.com/2015/01/chronic-fatigue-syndrome-rituximab-fluge-mella/

 

[Kati]

At this point for me, I don't want theories anymore. I want papers to publish. I want great physicians who will take care of me and my needs, who will listen carefully and suggest things which are within my philosophy of care.
I want access to lines of treatments to offer patients and options to switch to another line of treatment if plan A makes no difference.

In order to achieve this, we need:
1) coordinated and funded efforts for research and clinical trials.
2) a medical speciality, which includes ME at their yearly international conference, and includes questions regarding proper treatment and care at the final exams to enter the specialty. University hospitals teaching the disease to the medical students.
3) centers for excellence.
4) funding to find cause and subsets of the illness.

 

[A.B.]

a medical speciality, which includes ME at their yearly international conference, and includes questions regarding proper treatment and care at the final exams to enter the specialty. UNiversity hospitals teachimg the disease to the medical students.

More in general, I think what's needed is a medical speciality that deals with poorly understood multi symptom diseases. Right now this type of patient is likely to fall through the cracks of the health care system or end up being sent to psychiatrists in the belief that they are somatizing.

 

[Gingergrrl]

More in general, I think what's needed is a medical speciality that deals with poorly understood multi symptom diseases.

I agree and am afraid that if what is taught in medical schools re: ME/CFS is that people have flu-like malaise, chronic sore throat, immune deficiency, swollen lymph nodes, fever, night sweats, etc, then I do not meet a single one of those criteria but the term "poorly understood multi symptom disease" is the most perfect match for my experience than anything I have ever read. There needs to be a specialty that when we explain our symptoms, the doctor simply says, "I believe you" and here are the logical tests that we can run and treatments that we can try, regardless of what name or label we give the disease. I think we are all basically saying the same things in different ways.

 

[taniaaust1]

the thing that near everyone has EBV exposure. From wikipedia " In the United States, about half of all five-year-old children and about 90 percent of adults have evidence of previous infection.[9]"

the question is why does it keep possibly reactivating in us. Why are we getting sicker with this then often others do

I think the whole ME puzzle may go deeper then this. I personally think something may be wrong with our immune system.

 

[ScottTriGuy]

the question is why does it keep possibly reactivating in us. Why are we getting sicker with this then often others do

I am even less sciencey, but wonder if epigenetics is the other piece of the puzzle.

I'm thinking of this study... http://www.ncbi.nlm.nih.gov/pubmed/25111603

"We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology."

...because I chatted informally with the author a couple of weeks ago (we have a mutual friend who introduced us) - he will be releasing his latest research very soon - he used a larger ME sample and discerned 2 sub-groups in response to glucocorticoids - one group reacted normally, the other group reacted abnormally - sorry, that's the limit to my understanding and memory of what he said!

 

[frederic83]

Dr. Chia think it is the intracellular enterovirus infection IN the stomach (primary site) that is the cause of a subgroup of CFS sufferers.
C. pneumonia is an intracellular bacteria and can cause CFS. Isn't the common factor the intracellular infection? HHV6, 7 can do the same. EBV can also do it (EBV in a latent state can induce cancers (throat, stomach...) for example), but it is apparently more rare.


I would guess infected B-cell is a consequence.

About vitamin D, some feel well with it, others no. So I post this video of KDM. You just have to play it and listen to him a minute:

It is a question of ratio between 1,25 and 25 vit D. So supplementing vit D can worsen the state of some CFS sufferers. That would explain why some feel bad with it.

 

[Groggy Doggy]

At this point for me, I don't want theories anymore. I want papers to publish. I want great physicians who will take care of me and my needs, who will listen carefully and suggest things which are within my philosophy of care.
I want access to lines of treatments to offer patients and options to switch to another line of treatment if plan A makes no difference.

In order to achieve this, we need:
1) coordinated and funded efforts for research and clinical trials.
2) a medical speciality, which includes ME at their yearly international conference, and includes questions regarding proper treatment and care at the final exams to enter the specialty. UNiversity hospitals teachimg the disease to the medical students.
3) centers for excellence.
4) funding to find cause and subsets of the illness.

These are all excellent goals, but most will take many years to implement. In the meanwhile, we need to take matters into our own hands and find a doctor we are comfortable with to treat us. This will involve research, travel, time, patience, and money. The healthier we are, the more stamina we will have to fight for the goals we are passionate about.

If you need specific information about the experience of PR members, you can start a new thread (with a survey poll) and ask about doctors, doctors treatment options, doctor ability to listen, doctor ability to offer alternatives, doctors abilitiy to use diagnostics to match a treatment, costs for a doctor visit, costs for treatments, trust/confidence in doctor, location, % of recovery from using treatments, length of time seen doctor, number of years been sick, etc.

This information would be very helpful to many of us too.

GD

 

[Hip]

The absence of MECFS symptoms in HIV+ people, despite proliferation of herpes viruses.

That is a very interesting point.


All I have done with the idea presented in this thread is to identify a common characteristic found in the three viruses most commonly associated with ME/CFS: enterovirus, EBV and HHV-6. It is something of a mystery why, out of all the viruses that infect humans, only a small number are associated with ME/CFS.

What features do these small number of ME/CFS-associated viruses have that allow them to sometimes trigger ME/CFS?

So when I noticed that enterovirus, EBV and HHV-6 all appear able to infect B-cells, that grabbed my attention. It made me think that possibly B-cell infection is a prerequisite condition for ME/CFS to occur (especially if we assume that ME/CFS may be driven by autoimmune / autoantibody mechanisms triggered or facilitated by a viral infection of B-cells).



The shortcoming of this idea is that in the case of the coxsackievirus B (CVB) infection of B-cells, this has only been shown in a mouse model, as far as I am aware; and also, I am not sure if CVB infection of mouse B-cells is just an acute infection that is soon cleared up, or whether CVB can form a persistent long-term infection in B-cells. Since CVB does not possess the normal viral latency mechanisms, I would think that a long term CVB infection in B-cells would involve the non-cytolytic form of CVB.

Another shortcoming is that it probably would not explain the cases of ME/CFS or ME/CFS-like diseases from other pathogens such as parvovirus B19, Chlamydia pneumoniae, Giardia lamblia or Coxiella burnetii, which I don't think infect B-cells, as far as I am aware; however, it may be that these pathogens facilitate an autoimmune response by other mechanisms.

if someone had EBV as one of their main triggers and now presents with significant autoimmune abnormalities, would they be the best candidate for RTX?

I can't for the moment see how this speculative idea, even if it were correct, translates into treatment strategies. Perhaps some ideas will occur to me later.

It's more just looking at a possible reason why enterovirus, EBV and HHV-6 are the viruses most strongly linked to ME/CFS.

 

[Hip]

I wonder if that plays into impaired vitamin D pathways then?

Looks like something worth investigating, although I am not aware of any studies or anecdotal reports showing vitamin D (at least at normal doses) can help ME/CFS.

Although if you consider the Marshall Protocol, which some report has major benefits for ME/CFS, this is based on using the blood pressure drug Benicar (olmesartan) to potently activate the vitamin D receptor in cells.

 

[Gingergrrl]

I can't for the moment see how this speculative idea, even if were correct, translates to treatment strategies.

Thanks for your reply and my thought was just that what if there was a connection between starting with a virus like EBV that infects the B cells and ending up with autoantibodies (that you did not have before) that also invade (attack?) the B cells? Maybe RTX kills two birds with one stone? Or other autoimmune strategies? Like I said I lack any science to back this up and just a thought.

 

[Hip]

Maybe RTX kills two birds with one stone?

That certainly seems like a possibly: that rituximab not only kills off the autoantibody-producing B-cells, but may also kill of the B-cells containing latent EBV infection.

So if the B-cell infection were playing a role in autoimmunity (but remember this is just speculation), then perhaps killing off those infected B-cells (if rituximab can indeed do this) might fix autoimmune problems at a deeper level than just killing of the autoantibody-producing B-cells.


In terms of the number of B-cells infected, according to this paper, during mononucleosis, around 1 in every 10,000 B-cells gets infected with EBV; then the immune system responds, and kills off most but not all of these infected B-cells; afterwards you are left with around 1 in every 100,000 B-cells still infected with EBV, but EBV in a latent state (these cells with latent EBV infect are memory B-cells).

Dr. Chia think it is the intracellular enterovirus infection IN the stomach (primary site) that is the cause of a subgroup of CFS sufferers.
C. pneumonia is an intracellular bacteria and can cause CFS. Isn't the common factor the intracellular infection?HHV6, 7 can do the same. EBV can also do it

Being an intracellular pathogen that can live in cells or establish latency in cells appears to be a key factor (since nearly all ME/CFS-associated pathogens are intracellular), but I should think it depends on what cell types and what organs the pathogen can infect. For example, adenovirus, bornavirus, HHV-8, human papilloma virus and HIV establish a long term infection in cells, but have no known connection to ME/CFS.

One exception seems to be the many cases of ME/CFS triggered by the 1957 outbreak of Asian influenza A virus (subtype H2N2). Prof Gottries in Sweden saw hundreds of these patients at that time, and eventually got ME/CFS himself after catching this virus. As far as I am aware, influenzavirus does not create latency states.

Some more exceptions: I don't think Giardia lamblia is intracellular (it is a protozoan parasite), and Ross River virus I don't think can establish latency. But these exceptions are relatively rare triggers of ME/CFS.