Myalgic encephalomyelitis (ME) and HERVs

Viruses. Apparently there are quite a lot of them on this old rock we call home and I've started to become quite interested in some of them, or at least how we as a species have, and continue to interact with them down the ages.

I must start by thanking Natasa for bringing me into contact with the paper by Kenny De Meirleir and colleagues* (open-access) looking at human endogenous retrovirus (HERV) expression in a small cohort of patients diagnosed with myalgic encephalomyelitis (ME). I'm going to try and talk about this potentially quite important paper as best I can, bearing in mind my considerable non-expertise in all things HERVs and indeed, ME. And just in case you want another viewpoint on this study, the article by Joel (Snowathlete) is pretty good.

Voyage of Discovery @ Wikipedia  

OK, so HERVs. Think ghosts of viruses past, bits of which are communicated down the generations and comprise a very surprising 8% of the human genome. I've talked about HERVs before with autism and schizophrenia in mind (see this post) and the involvement of epigenetic means in keeping HERVs in some kind of check. Consider this post a bit of an extension of that discussion albeit with ME in mind. Consider also how some of the De Meirleir results might also be potentially investigated with autism and schizophrenia in mind.

Before progressing to the findings, the first thing that struck me about this paper is its point of origin: the Whittemore Peterson Institute. While this name probably means very little to many people, those with a particular interest in ME (and Chronic Fatigue Syndrome, CFS) will perhaps know about some of the recent history which included the WPI, and those magic letters X-M-R-V (see this post). I might add that this point should not in any way, shape or form alter or affect the findings or conclusions offered by De Meirleir et al. This is peer-reviewed stand-alone science. And science is after all [mostly] self-correcting; the XMRV story is quite a good example of that.

So back to the paper, and a very quick summary:

• The proposed connection between HERV expression in various conditions with an 'autoimmune' element** (systemic lupus erythematosus, SLE for example) led the authors to look at the expression of HERV proteins in gastrointestinal biopsies taken from 12 participants diagnosed with ME compared with those from 8 asymptomatic (at least for ME) control participants.
• Punch biopsies came from the stomach and duodenum and were analysed for "the presence of HERV and gamma-retroviral Env and Gag proteins" based on immunohistochemistry.
• Results: well alongside "the presence of substantial disruption of gut microbiota composition" in all ME cases (dysbiosis to you and me) and "a lympho-plasmatic infiltrate in the submucosa in all specimens"(question?), 8 of the 12 duodenal samples from participants with ME were immunoreactive to antibodies "raised against HERV proteins" compared with none of the controls. 
• Another quite important quote from the paper: "These observations suggest that the presence of the HERV protein in pDC's [plasmacytoid dendritic cells] may be associated with a pathological manifestation in at least a subset of individuals with ME".

I've probably not done justice to the final paper and the work that went into producing it with such a short summary. Nonetheless, I find these to be some quite exciting preliminary findings for quite a few reasons. I should point out that HERVs are seemingly becoming quite fashionable where ME and CFS are concerned as evidenced by the paper from Oakes and colleagues. I'll maybe come back to their findings on HERV-K in a later post.

Back to the De Meirleir paper and a few comments...

First is the suggestion that words like 'autoimmunity', 'antigen-presentation', 'inflammation' and 'gastrointestinal' might actually be part and parcel of the pathology of at least some cases of ME or at the very least, significant comorbidity. Accepting the continuing issue of definition and criteria for definition when it comes to ME (and CFS), and that there is still lots of debate as to what the underlying causes of ME might be and best treatment options are, I find myself drawn back to some of the work done in autism research; particularly that connected to the almighty MHC. Without going over already trodden ground, the MHC is perhaps best described as the way the body tells the immune system what is self and what is a foreign contaminant (to borrow a phrase from Disney's WALL-E). I note for example that MHC class II antigens have been talked about before, at least in CFS, as per the paper by Smith and colleagues*** (open-access).

As Meirleir points out, HERV proteins should normally be treated as 'self' by the MHC. They speculate however that several elements combine: (i) "Inflammation is known to increase HERV expression", (ii) "some HERV proteins act as superantigens", (iii) "pDCs are most remarkable for their ability to produce copious amount of type-1 IFN" and how an issues with pDC response might impact on interferon production with some potentially important knock-on effects****. Perhaps some food for thought?

Next is the possibility of a relationship between ME and that bright new discipline of epigenetics, bearing in mind the concept of jumping genes and the mantra: hypomethylation = more genomic instability with the connection back to HERVs. I should caution that nothing is specifically mentioned about epigenetics in the De Meirleir paper given their focus on identifying immunoreactivity to HERV protein in cases. Indeed I was very surprised to see that a PubMed search of the keywords 'myalgic encephalomyelitis and epigenetics' showed only 2 hits (20/02/13). An unexplored area if ever there was one....

Finally, I can't end this post without referencing the gut bacteria findings and indeed the fact that "Gastritis (mainly antritis) was present in all cases". Some years ago, two colleagues of mine speculated that within the spectrum of ME/CFS there seemed to be two primary phenotypes: one where symptoms appeared to coincide with gastrointestinal (GI) issues; another with a more neurological presentation - the word 'brain fog' seemed to be quite a well-used description. Now I'm not saying that these categorisations are entirely accurate, but certainly the GI symptoms element does seem to cropping up in quite a bit of the ME/CFS literature as for example in the paper by Clark and colleagues***** (full-text) on reports of things like childhood gastrointestinal symptoms potentially being risk factors for a diagnosis. Indeed, the overview provided by Lakhan & Kirchgessner****** (full-text) on gut inflammation and CFS covers quite a lot of the material in this area and again, a call for quite a bit more research to be done too.

The De Meirleir paper, whilst small in participant numbers and preliminary in nature is an interesting one; of that there is no doubt. The next stage of the HERV-ME journey - learning the lessons of XMRV - is independent replication with the appropriate statistical power and relevant control groups (fibromyalgia and various other autoimmune related conditions for example) and then, depending on those results, the real adventure can begin.

But also I would caution that we not forget all the other areas of potential importance to ME and CFS... (see here and here and here and here) in our prospective new-found fixation with HERVs and ME.

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* De Meirleir KL. et al. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In Vivo. 2013; 27: 177-187.

** Balada E. et al. Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity. Rev Med Virol. 2009; 19: 273-286.

*** Smith J. et al. Association of chronic fatigue syndrome with human leucocyte antigen class II alleles. J Clin Pathol. 2005; 58: 860–863.

**** Martinet J. et al. Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection. Gastroenterology. 2012; 143: 1586-1596.

***** Clark C. et al. Premorbid risk markers for chronic fatigue syndrome in the 1958 British birth cohort. Br J Psychiatr. August 2011.

****** Lakhan SE. & Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010; 7: 79.

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KENNY L. DE MEIRLEIR, SVETLANA F. KHAIBOULLINA, MARC FRÉMONT, JAN HULSTAERT, ALBERT A. RIZVANOV, ANDRÁS PALOTÁS, & VINCENT C. LOMBARDI (2013). Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins In Vivo, 27 (2), 177-187