ME/CFS and GWI patients exhibit increased humoral responses to the Herpesviruses-encoded dUTPase

[hixxy]

J Med Virol. 2017 Mar 17. doi: 10.1002/jmv.24810. [Epub ahead of print]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness patients exhibit increased humoral responses to the Herpesviruses-encoded dUTPase: Implications in disease pathophysiology.

Halpin P, Williams MV, Klimas NG, Fletcher MA, Barnes Z, Ariza ME.

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) are debilitating diseases with overlapping symptomology and there are currently no validated tests for definitive diagnosis of either syndrome. While there is evidence supporting the premise that some herpesviruses may act as possible triggers of ME/CFS, the involvement of herpesviruses in the pathophysiology of GWI has not been studied in spite of a higher prevalence of ME/CFS in these patients. We have previously demonstrated that the deoxyuridine triphosphate nucleotidohydrolases (dUTPase) encoded by Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and varicella-zoster virus (VZV) possess novel functions in innate and adaptive immunity. The results of this study demonstrate that a significant percentage of patients with ME/CFS (30.91-52.7%) and GWI (29.34%) are simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or the human dUTPase when compared to controls (17.21%). GWI patients exhibited significantly higher levels of antibodies to the HHV-6 and human dUTPases than controls (p = 0.0053 and p = 0.0036, respectively), while the ME/CFS cohort had higher anti-EBV-dUTPase antibodies than in both GWI patients (p = 0.0008) and controls (p < 0.0001) as well as significantly higher anti-human dUTPase antibodies than in controls (p = 0.0241). These results suggest that screening of patients' sera for the presence of various combinations of anti-dUTPase antibodies could be used as potential biomarkers to help identify/distinguish patients with these syndromes and better direct treatment. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:
Chronic Fatigue Syndrome; Epstein-Barr virus; Human herpesvirus 6; antibodies; deoxyuridine triphosphate nucleotidohydrolase; varicella-zoster virus

https://www.ncbi.nlm.nih.gov/pubmed/28303641
http://onlinelibrary.wiley.com/doi/10.1002/jmv.24810/abstract

 

[Kati]

Exciting! We are getting closer.

 

[anciendaze]

Now, if only we can connect this to research on metabolic abnormalities, we might start to think about prevention and cures.

 

[A.B.]

Exciting! We are getting closer.

Can you explain how this ties in with other recent research?

 

[M Paine]

Full paper -> http://sci-hub.cc/10.1002/jmv.24810

More or less, they are suggesting that reactivation of EBV, VZV, or HHV-6A is a result of the immune system failing in CFS/ME and GWI. In addition, that auto-reactive anti-bodies against human dUTPase may contribute to disease in some patients. I can't really see any flaw in that logic, it's nice that they don't attest to this being causative. How much the human dUTPase anti-bodies contribute to disease, who knows.

Our study demonstrates for the first time, the presence of autoantibodies against the human dUTPase in a subgroup of patients with ME/CFS and GWI

Our study demonstrates that a subgroup of patients diagnosed with either ME/CFS or GWI exhibited a statistically significant elevation in antibodies against the HHV-6, EBV and VZV encoded dUTPases, proteins that are only expressed during lytic or abortive lytic replication of these viruses, as well as the human nuclear dUTPase. These results suggest that in this subgroup of patients there is reactivation of multiple herpesviruses; a feature that is also observed in some transplant recipients [Shiley et al., 2010; Inazawa et al., 2015] and patients with drug-induced hypersensitivity syndrome (DISS/DRESS) [Shiohara et al., 2006; Picard et al., 2010; Chen et al., 2015]. Since GWI patients were exposed to a variety of chemical agents and environmental toxins a DIHS/DRESS-like reaction could contribute to the reactivation of herpesviruses, especially HHV-6 in these patients. While the mechanism(s) responsible for the simultaneous reactivation of these herpesviruses is unknown, it suggests a loss of immunological control primarily, at the CD8+ T-cell level. This is supported in part by a study demonstrating deficient EBV-specific T-cell responses in some ME/CFS patients [Loebel et al., 2014].

Our working model (Fig. 3), which is a modification of the latent viral immune inflammatory response (LVIIR) model for multisystem illnesses including GWI and ME/CFS [Maloney et al., 2013], shows how disruption of normal immune homeostasis allows for the increased abortive reactivation of the herpesviruses and release of virus-encoded dUTPases by pyroptosis or in exosomes.

I'm not so sure about their model in fig 3... I would have thought "Disruption of Immune Responses" would have included reduced NK cell/T-cell function, but instead they show that as a byproduct of viral cell lysis. Someone correct me if I'm wrong, but reduced NK function is more ubiquitous among patients than co-morbid viral reactivation. Which seems to suggest that it may be more closely tied to the etiology of this disease, rather than a downstream consequence of viral reactivation.

 

[Kati]

Can you explain how this ties in with other recent research?

No, @A.B. sorry I can't. I am no scientist.

 

[A.B.]

No, @A.B. sorry I can't. I am no scientist.

No problem, it sounded a bit as if you were seeing a connection.

 

[Kati]

No problem, it sounded a bit as if you were seeing a connection.

Here is my train of thought. DR Klimas and a few others like Peterson, Kogelnik and Montoya have known for a while now about the implication of herpes viruses in the pathogenesis/pathology of ME. Here, they are providing novel mechanisms.

I have no doubts that it ties in with other groups' latest research. Dr Klimas will speak at Invest in ME this year and can't wait to hear what she will have to say.

So like I said, I cannot tie in scientifically, it is out of my scientific limits.

 

[RogerBlack]

Full paper -> http://sci-hub.cc/10.1002/jmv.24810

More or less, they are suggesting that reactivation of EBV, VZV, or HHV-6A is a result of the immune system failing in CFS/ME and GWI. In addition, that auto-reactive anti-bodies against human dUTPase may contribute to disease in some patients. I can't really see any flaw in that logic, it's nice that they don't attest to this being causative. How much the human dUTPase anti-bodies contribute to disease, who knows.

Are they?
I only skimmed the abstract, but surely the same result would happen if you got an auto-antibody generated against the virus (or other causative or auto-antigen triggering agent) at the time of infection, and then that is entirely causing all of the pathology going forward.
Stress (of whatever form) causes the auto-antibody to flare.

 

[M Paine]

I just noticed that they used Optical Density as their measurement of antibody titres from their ELISA screening. This is really not enough to determine the quantity of antibody in these samples.

 

[hixxy]

I just noticed that they used Optical Density as their measurement of antibody titres from their ELISA screening. This is really not enough to determine the quantity of antibody in these samples.

Klimas is an immunologist no?

 

[M Paine]

Klimas is an immunologist no?

Yes, but the lead author(s) seem to be out of a different lab. I wouldn't be suprised if she, or any other reviewers may have pointed out the limitations of using OD for quantitative analysis.

 

[M Paine]

Are they?
I only skimmed the abstract, but surely the same result would happen if you got an auto-antibody generated against the virus (or other causative or auto-antigen triggering agent) at the time of infection, and then that is entirely causing all of the pathology going forward.
Stress (of whatever form) causes the auto-antibody to flare.

Only 7 out of 55 ME patients screened positive for human dUTPase reactive antibody. 7 out of 151 controls also screened positive.

They observed no evidence of molecular mimicry:

It is unlikely that the observed humoral response to the human dUTPase is due to cross-reactivity with the herpesviruses-encoded dUTPases since there is little homology between the homotrimeric human dUTPase and the monomeric herpesviruses dUTPases. Further antibody characterization studies using polyclonal antibodies against the EBV-encoded dUTPase revealed no reaction with the human dUTPase (data not shown).

The paper is suggestive of some other breakdown in immune regulation allowing for viral reactivation, and increased incidence of auto-reactivity.


Have a full read yourself, I'd be interested to hear what you come away from this paper with.

 

[ash0787]

I had a bad viral flare up a few days ago which made me feel like I was going to pass out, nausea etc,
it passed fairly quickly but it was clear to me that in the following days the immune system was overactive,
I noticed changes to the area of my finger which usually indicates a sort of auto immune attack and originally coincided with a deterioration of function level. Since then I have felt extra tired and especially rough in the morning, I tend to struggle a lot more with viruses like colds etc than I used to, I usually have to reduce activity level for about a week after. I do worry that one of these times its going to cause a more longer term recalibration of the immune system which will make the disease worse.

 

[AndyPR]

Article - https://hhv-6foundation.org/cogniti...ential-biomarker-for-gulf-war-illness-and-cfs

Herpesvirus-encoded dUTPases can trigger modulation of genes involved in chronic inflammation, T-cell function, and neurotransmitter function. A group from Ohio State University led by Maria Aziza, PhD, found that antibodies to HHV-6 and VZV dUTPases were significantly elevated in Gulf War Illness (GWI) patients compared to controls. EBV dUTPase antibodies were elevated in Chronic Fatigue Syndrome (CFS) patients. Also, the CFS and GWI groups exhibited increased autoimmunity; 15% of CFS and 39% of GWI patients had autoantibodies against human dUTPase, compared to 4.7% among controls.

As the herpesvirus dUTPases are only expressed during viral replication or active “abortive” infection, they are a good indicator of viral activity. 49% of CFS patients co-expressed antibodies to both HHV-6 and EBV dUTPases, and 55% were positive for HHV-6. 31% expressed anti-human (autoantibodies) and anti-HHV-dUTPase antibodies together. Similarly, the GWI cohort exhibited a significant increase in anti-HHV-6, anti-VZV, and anti-human dUTPase antibodies compared to controls.