All posts tagged autoimmune

The Autoimmune Virus? Groundbreaking EBV Finding Could Help Explain ME/CFS

Viral Mystery 

“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” Harley

I sensed some awe in Ron Davis’s voice as he pushed for more understanding of Epstein-Barr Virus’s effects in ME/CFS during a talk at the Brain Science conference.  Davis is not to my knowledge finding much evidence of EBV reactivation in the severe ME/CFS patient study – a surprise – but he is very interested in what happened during that initial EBV infection, which appears to have triggered chronic fatigue syndrome (ME/CFS) in so many people.

Epstein-barr chronic fatigue

A large, complex and very common virus, EBV is responsible for infectious mononucleosis and appears to contribute to numerous autoimmune disorders.

He’s not alone in his “admiration” for the virus. Simmaron’s Advisor, Dr. Daniel Peterson, whose clinical practice and research stemmed from an outbreak in the Lake Tahoe region of Chronic Fatigue Syndrome, has tracked EBV in patients for decades, noting very high titers to EBV and other herpes viruses in subsets of patients.

It’s not surprising that these two important figures have had their eyes on EBV. EBV, after all, is kind of in a league of its own.  An invader of B and epithelial cells, the 50th anniversary of its discovery was recently celebrated with numerous reviews.  Epstein-Barr was discovered in 1966 by Anthony Epstein and Yvonne Barr. It was the first human virus shown to cause cancer. The sequencing of its large genome in 1995 helped launch the genomic era.

One of the more massive and complicated viruses, it’s one of the very few viruses that’s able to avoid elimination: once EBV infects your B-cells, it’s in your body to stay. It’s able to effectively hide from the immune system and reactivate just enough so that when the infected B-cells die it can move on to other cells.

We’re well equipped to ward off EBV when we’re young – it usually produces only minor symptoms – but as our immune systems alter as we age, that changes.  Encountering EBV as an adolescent or adult (infectious mononucleosis, glandular fever)  – as increasingly happens in our germ phobic age – often means months of convalescence as our immune systems struggle to ward off this powerful virus.

The problems don’t stop there. We know that infectious mononucleosis (IM) is a common trigger of ME/CFS but coming down with IM/glandular fever in adolescence has also been shown to increase one’s risk of coming down with multiple sclerosis 2-4 fold and lupus by fifty percent.  Because of EBV’s ability to remain latent in the body, EBV reactivations are a huge problem for transplant patients with compromised immune systems.

The big question concerning EBV is how a virus which has essentially been latent for decades could contribute to serious diseases like MS and lupus. We now may have the answer. Last week, what will probably turn out to be a seminal paper in pathogen research directly showed for the first time how EBV appears to be able to trigger autoimmune diseases later in life and could conceivably play a role in ME/CFS.

The rather hum drum title of the paper “Transcription factors operate across disease loci with EBNA2 implicated in autoimmunity” in the Nature Genetics Journal hardly hinted at the possibilities the paper presents.

Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity John B. HarleyXiaoting ChenMario PujatoDaniel MillerAvery MaddoxCarmy ForneyAlbert F. MagnusenArthur LynchKashish ChetalMasashi YukawaArtem BarskiNathan SalomonisKenneth M. KaufmanLeah C. Kottyan & Matthew T. Weirauch. Nature Genetics (2018) doi:10.1038/s41588-018-0102-3

EBV  consists of several proteins of which EBNA-2 is one. EBNA-2 is EBV’s main viral transactivator; i.e. it’s a transcription factor that turns on genes in an infected cell that help EBV to survive. Essentially EBNA-2 allows EBV to hijack a cell’s genetics and put them to its own use.

The study – produced by researchers at Cinncinnati’s Children Hospital – demonstrated that once EBV infects B-cells, it turns on genes that have been identified as risk factors for a boatload of autoimmune diseases.

It turns out that even though the virus is, so to speak, latent; i.e. it’s not replicating – its transcription factor is still active  – altering the expression of our genes. The genes that it affects just happen to be the same genes that increase the risk of developing lupus, multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes.  Apparently decades of genetic assault from EBV’s transcription factor can set the stage or at least contribute to many autoimmune diseases.

Chronic diseases are usually caused by a variety of genetic and environmental factors. Because not everyone with these transcription factors comes down with a chronic illness, other factors must play a role. The authors believe, though, that the gene expression changes induced by the virus in the B cells could account for a large number of people with lupus and MS who fall ill.

“In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases,” Harley

Chronic Fatigue Syndrome and EBV/Infectious Mononucleosis – A Short History

Researchers have been trying to figure out – mostly unsuccessfully- what the heck happens to plunge people with infectious mononucleosis into ME/CFS for quite some time.

trigger

Infectious mononucleosis/glandular fever is believed to be a common trigger of ME/CFS

In fact, infectious mononucleosis/glandular fever was probably the first disease associated with ME/CFS. Studies in the mid-1990’s, including one from the CDC, suggested ME/CFS was, at least in part,  “chronic infectious mononucleosis” or “chronic mononucleosis syndrome“.  Even Stephen Straus penned a paper on the “The chronic mononucleosis syndrome“.

Straus’s small 1989 study reporting high rates of psychiatric diagnoses in ME/CFS patients prior to their becoming ill set a theme in motion which was disproved by two Peter White  ME/CFS IM publications.  White found IM/glandular fever to be a particularly strong trigger of ME/CFS which he concluded was probably responsible for about 3,000 new cases of ME/CFS a year in the U.K.

A 1992 Swedish study began a trend of examining people with ME/CFS during infectious mononucleosis and afterwards in order to try and determine what happened. That study concluded that whatever happened was not due to EBV reactivation.

In 2010 Taylor found reduced peak oxygen consumption during exercise in adolescents with ME/CFS after IM compared to IM patients who had recovered. Broderick’s finding of altered cytokine networks associated with Th17 in ME/CFS patients following IM suggested immune dysregulation had occurred.

Glaser’s 2005 study suggested that an EBV encoded enzyme produced by a non-replicating form of EBV could be producing symptoms in ME/CFS.  Lerner’s 2012 study suggested that antibodies to two EBV produced proteins were commonly present in ME/CFS – suggesting that a prolonged immune reaction to EBV might be occurring in ME/CFS as well.

In 2014 Loebel/Scheibenbogen suggested that ME/CFS patients may be having difficulty controlling the early stages of EBV reactivation.   Loebel’s 2017 follow up study suggested that ME/CFS patients’ immune system might be over-reacting to an EBV produced protein and that autoimmunity might be involved.

Leonard Jason’s large IM college student study will hopefully provide clues why some people never recover from it. He’s completing data analysis of a study examining college students who came down with infectious mononucleosis and then ME/CFS. So far Jason has found that at least 4-5% of college students come down with IM while at school.

Treatment Implications

Interestingly, several drugs that are available can block some of the transcription factors EBV has inserted into B-cells.  (I was unable to determine what they are.) The authors also hope the study will help spur more efforts to produce an EBV vaccine.

Next For ME/CFS and EBV

Now that we have evidence that EBV/IM contributes to many autoimmune diseases, it’s hard to think that ME/CFS is not somehow involved. Chronic fatigue syndrome is different in that infectious mononucleosis (and other infections) immediately triggers ME/CFS in many people. What we don’t know is if bouts of IM also trigger ME/CFS 5, 10, 15 or more years later as occurs in these other disorders.

Opportunities for Collaboration Open Up

The big question awaiting ME/CFS now is if the abnormal transcription factors associated with the autoimmune diseases in the recent paper are present. The good news is that a study determining that appears to be within reach of an ME/CFS researcher with the technical ability and funds. In an unusual move, the Cincinnati researchers are making the computer code they used available to other researchers.

“We are going to great lengths to not only make the computer code available, but all of the data and all of the results. We think it’s an interesting approach that could have implications for many diseases, so we’re contacting experts on the various diseases and sharing the results and seeing if they want to collaborate to follow-up on them.” Weinrauch

“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders” Harley

Collaboration

The Cinncinnati team is providing its computer code free to other researchers

They believe EBV will be implicated in many more diseases, and there is already some evidence that it is.  Using the same analytical techniques, they’ve already identified 94 other diseases including many non-autoimmune diseases in which EBV may play a role.

This is one of the few studies in which the researchers are so jazzed by their results that they’ve dropped all pretenses to modesty. The study results need to be validated, but because EBV is so common and is potentially linked to so many autoimmune (and other diseases), it has the potential to rewrite our understanding of how autoimmune diseases arise. The authors fully recognize the potential importance of their finding. The lead author of the study, John Harley, said:

“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” Harley

One of the senior authors of the study stated:

“This same cast of characters is a villain in multiple immune-related diseases. They’re playing that role through different ways, and doing it at different places in your genome, but it’s the same sinister characters. So if we could develop therapies to stop them from doing this, then it would help multiple diseases.” Matthew Weirauch

 

Hope for an ME/CFS Autoimmune Subset: A German Researcher Steps Forward

German Researcher Steps Up

Carmen Scheibenbogen MD is another sign that the ME/CFS field is slowly but surely hopefully catching on. Scheibenbogen is relatively new to this field, but she’s not new to medical research. A trained oncologist and hematologist as well as a physician and Professor of Immunology in Berlin, her research resume includes over 150 publications dating back 25 years.

scheibenbogen

Dr Scheibenbogen has identified what she believes is an autoimmune subset in ME/CFS. (Image from Invest in ME)

In short, she’s a respected and established researcher, and one from Germany to boot. (I can’t remember the last German researcher to take on ME/CFS.) Her path to ME/CFS has not been an easy one. Germany hardly acknowledges ME/CFS as a disease, and doesn’t fund ME/CFS research – if I’m reading her right, there is apparently literally no avenue to apply for ME/CFS research funding there.

Yet she’s very quickly become one of our most prolific researchers. Over the past four years her team has published no less than seven papers, has won two Ramsay Awards, and played a central role in the development of the new European Research collaboration, EUROMENE. Her biosketch lists CFS/ME, Immunodeficiency, and Cancer Immunology as her main research interests.

Scheibenbogen’s first ME/CFS publication In 2014 found ME/CFS patients mounting a feeble response to Epstein-Barr virus (EBV) . The reduced response to EBV reactivation could help explain the ups and downs seen, particularly during stressful situations.

In 2016, figuring that when Rituximab worked in ME/CFS it probably did so by whacking antibody producing B-cells, her group examined antibodies against a variety of receptors that affect blood flow, the autonomic nervous system, etc. They found that about 30% of ME/CFS patients in a large study (n=293) had increased levels of antibodies to adrenergic (B2) and/or muscarinic M3/M4 acetylcholine receptors (M3/M4).

That suggested that the immune systems of a significant subset of ME/CFS patients might be attacking the receptors on cells which regulate blood flow, lung functioning, muscle contractions and attention. Furthermore, the finding (a “remarkable” one they said) that the antibody levels of two receptors correlated with a host of immune factors (immunoglobulin levels, T cell activation, elevated ANA, TPO antibodies) suggested that this subset of ME/CFS patients are suffering from an autoimmune disease. Scheibenbogen has suggested that the kind of ME/CFS you have may be dependent on the kind of autoantibodies present in your system.

See Bad Bacteria, Brainstem Abnormalities and Progress with Rituximab: the Invest in ME Conference

Similar antibody findings have been found in a range of diseases (postural tachycardia, regional pain syndrome, Alzheimer’s, Sjogren’s syndrome, asthma) some of which have been associated with ME/CFS.

They also noted that immunoadsorption factors that are able to mop up these antibodies had proven to be helpful in some diseases. Two years later they put that idea to the test.

Possible Autoimmune Treatment

PLoS One. 2018 Mar 15;13(3):e0193672. doi: 10.1371/journal.pone.0193672. eCollection 2018.
Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME.Scheibenbogen C1,2, Loebel M1, Freitag H1, Krueger A3, Bauer S1, Antelmann M1, Doehner W4, Scherbakov N4, Heidecke H5, Reinke P2,3, Volk HD1,2, Grabowski P1.

Adsorption

Adsorption vs absorption – By Daniele Pugliesi – File:Absorbimento e adsorbimento.svg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20486772

They used a blood purification technique called immunoadsorption to eliminate the B2 antibodies from people with ME/CFS who’d had a post-infectious onset and high B2 antibody levels. Immunoadsorption (IA) was given five times over seven days to completely wash out the antibodies. Over the next six months the participants’ symptoms, muscle strength, endothelial functioning and immune factors were watched.

Findings

Significant improvement eventually followed by a relapse was the order of the day. One patient who could barely walk prior to the treatment was able to walk several hundred yards at the end of the IA process. She completely recovered for seven weeks and then relapsed. Another patient improved enough to go back to work but then relapsed. Five patients who improved started to relapse by the end of the six months. Three patients – a good third of the study – felt significant improvements in fatigue lasting at least 12 months.

The levels of all four antibodies (B1, B2, M3 and M4) declined after the treatment in all 9 participants. These are good results which are hampered by the small sample size and lack of a placebo control. Through our experiences with Rituximab, Synergy and Mirogabalin we’ve learned how little to trust early results.  Still, research has to start somewhere and the results thus far present hope for a significant subset of ME/CFS patients.

Present and Future Work

Ramsay Award Standout

The Solve ME/CFS Initiative (SMCI) provides funding to five or so researchers every year in its Ramsay Awards. The Awards are quite competitive with SMCI receiving far more applications than it can fund, but over the past two years the Scheibenbogen group has won two – the only group to do so.

2016 Award

Citing “ample evidence of an autoimmune pathomechanism” the Scheibenbogen team will be digging into the genetics of their “autoimmune subset”. They’ll be determining if genetic abnormalities in the enzymes or transcription factor that turn on the autoimmune processes are present. They’re also analyzing the immune cells (dendritic cells, regulatory B-cells) known to produce autoimmune responses.

This is one of the first times that I’m aware of that a research group has targeted a subset and dug deeper into it.  Scheibenbogen’s focus is clearly good news for people in that subset but it’s also good news for people outside of it. If she’s found a robust subset then it needs to be peeled off from other ME/CFS patients because it’s undoubtedly confounding study results for those patients.

2017 Award

The 2017 Ramsay Award will determine if T-cells and monocytes are up to the task in ME/CFS. We know that NK and probably T-cells are laggards in ME/CFS patients’ immune systems, but other immune cells are largely untested.

Following on recent findings of impairments in energy production, the Scheibenbogen group is going to determine if T-cells and monocytes have the energy to spring into action when needed. Immune cells are mostly quiescent until they come across a pathogen, at which point they’re required to rev up their engines and explode into action. If they don’t have the energy to “explode” they’ll have difficulty fighting off bugs.

If I have it right, they’re also going to stimulate cells using adrenergic and acetylcholinergic factors to see if they affect their metabolism or energy production. Given the role these factors appear to play in the deranged stress response found in ME/CFS, finding a metabolic tie-in would be exciting indeed.

Simmaron Scheibenbogen Collaboration Underway

The Simmaron Research Foundation is also working with Dr. Scheibenbogen to identify the subset of Dr. Peterson’s patients who fit the autoimmune profile, and to further characterize the subset from a clinical perspective.

A Leader

Over the past five years Scheibenbogen has become deeply immersed in ME/CFS. She was the lead author of a paper on the EUROMENE network, which contains researchers and clinicians from 17 European countries. Euromene was accepted into the COST (Cooperation in Science and Technology) framework which was established by the European Union to support collaboration in scientific endeavors. While COST does not fund research studies, it does fund networks and provides networking possibilities across the European Union.

EUROMENE members

EUROMENE members

One goal of Euromene COST Action is to establish a “sustainable integrated network of researchers in Europe working in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and to promote cooperation between research groups.

Coordination and collaboration appears to be becoming a bigger and bigger theme. The OMF and the SMCI held collaborative and networking meetings last year. The NIH research centers are collaborating on one large project. Canada’s May Montreal conference is focusing on establishing cooperative efforts to understand ME/CFS. (Dr. Scheibenbogen will be attending.) The OMF’s next conference is set for September of this year.

However Dr. Scheibenbogen got interested in ME/CFS, it’s great to see her get so involved so quickly. She reminds me of another relatively new researcher in the field – Dr. Maureen Hanson – who quickly cranked out research studies and is now leading an NIH ME/CFS research center. It’s good to see new researchers have success in this field.

Of course, the going is still tough. In an SMCI interview Dr. Scheibenbogen seemed astonished at the lack of opportunities for research into what she described as a frequent and severe disease.

But still the situation is very disappointing with so little support for patients and research and almost no interest from pharmaceutical companies to perform clinical studies. I am a trained oncologist and hematologist and there the situation is so different with so much research and drug development.

Like everyone else in this field, Dr. Scheibenbogen is a pioneer and pioneers by definition have rough going. Like the pioneers of old she’s forging a path through some hostile territory, not as the pioneers did in the old West but this time German medical circles.  Her work is getting results, though, results that her colleagues will surely notice.  Here’s to a new presence in the field who’s put, perhaps for the first time, Germany – the most powerful nation in Europe – on the ME/CFS map.

Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities.” Dr. Mady Hornig. 

The Subset Makers

Simmaron Research | Scientifically Redefining ME CFS | #ShakeTheCFSstigmaOver the past couple of years the Simmaron Research Foundation and Center for Infection and Immunity at Columbia University and others have begun to pump out some long awaited subsets. This week, new findings were published by Columbia and Simmaron that define 2 subsets.

They’re not the usual suspects (infectious trigger vs non-infectious trigger; gradual onset vs acute onset). In fact, they involve subsets few would have predicted a couple of years ago. They suggest that we might be in for some real surprises over time.

Short Duration vs Long Duration Subset: Two years ago, the Simmaron Research Foundation collaborated with Ian Lipkin and other doctors to uncover a subset few had anticipated: short duration patients vs long duration patients.

The Atypical Patient or “Peterson Subset”:  Now comes a subset of atypical chronic fatigue syndrome (ME/CFS) patients (the “Peterson Subset”) that Dr. Peterson had long wondered about. These patients had ME/CFS but tended to follow a different course. Some had had unusual exposures (unusual infections, blood transfusions); others developed serious illnesses (cancer, autoimmune diseases, etc.) that Dr. Peterson didn’t see in the rest of the population.

Dr. Hornig talked about how the atypical subset came about. Like so many breakthroughs in medicine it took a careful and observant doctor/researcher to bring it about. This study, she said, was a testament to:

“Dr. Peterson’s clinical acumen, his long-term follow up of this patient population and his attentiveness to the full range of complex, serious medical disorders that might develop. The classical group had been followed for similar lengths of time but had not developed these more severe, serious comorbidities.”

The atypical vs classical distinction was pre-established by Dr. Peterson before the analysis. Based on his wide-ranging clinical experience, the atypical group stood out for either: 1) the presence of unusual precursors (triggers) of ME/CFS or; 2) the development of more unusual and severe comorbidities over varying (and often long-term) intervals after ME/CFS onset.”

atypical subset

The atypical group turned out to be quite different

Dr. Peterson felt the unusual outcomes weren’t just the result of chance: something different was going on – something that he felt as a doctor needed to be identified. What if, he thought, there was a way to identify these unusual patients before they started developing these significant illnesses. Then he could do more extensive cancer or immune screens and watch these patients more closely.

Plus, these patients could be inadvertently bollixing up the results of ME/CFS studies. Peterson was so sure, in fact, this subset was different that he had its effects assessed during the first Simmaron/CII spinal fluid study. Peterson turned out to be right: the atypical subset had such an effect on the results that it had to be removed.

The next step was a study comparing the two groups. Using Dr. Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that “Peterson Subset” not only had markedly different immune findings but displayed a different pattern of immune results as well. Dr. Peterson is Scientific Advisor to Simmaron and Gunnar Gottschalk was its Research Manager.

Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations M Hornig1,2, CG Gottschalk3, ML Eddy1, X Che1, JE Ukaigwe1, DL Peterson3 and WI Lipkin. Translational Psychiatry (2017) 7, e1080; doi:10.1038/tp.2017.44; published online 4 April 2017

 The Atypical Subset

What does a typical chronic fatigue syndrome (ME/CFS) patient look like? Something like someone who suddenly comes down with a flu-like illness and never recovers. They may get better or they may get worse, but they don’t come down with cancer, an autoimmune illness, seizures or other significant illnesses.

An atypical patient, on the other hand, might have a history of viral infection (viral encephalitis) or have been exposed to unusual pathogens during foreign travel or had a blood transfusion before becoming ill. They also tended to be more severely cognitively impaired and had more neurological complaints.  They tended to suffer from severe diseases as well.

Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis these patients looked like a typical ME/CFS patient. This study suggests, though, that very early on, something different was happening in their central nervous systems.

The Atypical Patients in the Study (the “Peterson Subset”):

  • Atypical multiple sclerosis – 3
  • Other autoimmune/inflammatory disorders – 4
  • Cancer – 8 (brain-3, breast-2, lymphoma -2, pancreatic-1)
  • Infections – 2 (West Nile Virus encephalitis – 1; Unspecified viral encephalitis – 1)
  • Illness during foreign travel – 2
  • Illness after blood transfusion – 1
  • Seizure disorder – 6
  • Gulf War Illness – 1

Immune “Exhaustion”?

This “broadly based” immune study compared 51 cytokines and other immune factors in the cerebral spinal fluid of 32 typical and 19 atypical ME/CFS patients. These numbers at first glance may seem small but they’re actually quite large for spinal fluid studies.

The Simmaron Research Foundation/Center for Infection and Immunity’s prior studies suggested that typical ME/CFS patients’ immune systems went on high alert for the first couple of years of illness but then went into slumber mode. In fact, it was more than slumber mode: their immune activity essentially tanked – leading to the hypothesis that frantic activity of the first couple of years might have left their immune systems depleted.

autoimmune diseases

Autoimmune diseases were amongst the unusual comorbidities found in the atypical subset.

This study suggests that the “Peterson Subset” follows a markedly different pattern. The major burst of immune activity early on followed by equally dramatic downturns found in the typical patients is gone. Instead the study suggests that the immune systems of the atypical patients essentially started off low and stayed low.

Almost half the immune factors tested (IL1β, IL5, IL7, IL13, IL17A, IFNα2, IFNγ, TNFα, TRAIL (TNFSF10), CCL2, CCL7, CXCL5, CXCL9, CSF3 (GCSF), βNGF, resistin, serpin E1) were lower early in the illness in the atypical group.

As the illness proceeded, though, the pattern changed again: the atypical groups’ immune system actually revved up again.

When I asked if immune exhaustion was bringing the immune system down early in the atypical group, Mady Hornig replied:

 “We don’t know yet. Our additional finding of an interaction of diagnostic subset with duration of illness – wherein the atypical group showed a pattern of increased levels of immune molecules with longer duration of illness, as opposed to the dampened immune profiles in the classical group with longer illness duration compared to classical ME/CFS in the early stages of disease  (as we had seen in the immune profiling work based on plasma samples) – suggests that the response tends to be more suppressed at the onset of ME/CFS in the atypical group.”

Could that dampened immune response early in their illness be contributing to the illnesses the atypical group experienced later? Dr. Hornig again cautioned about the need to replicate the study but suggested it might.  A viral trigger could have blasted their immune systems or vice versa – a problematic immune system could have allowed a virus in …

 “However, dampening of inflammatory (so-called Th1/Th17-type) responses might be expected to restrict an individual’s ability to keep problematic microbes from replicating. Certain viruses – even common ones implicated in ME/CFS in some studies, such as Epstein-Barr Virus (EBV) – are well-known to be associated with development of certain cancers; however, only a fraction of those infected with EBV develop cancers.

It is a bit of a chicken-egg conundrum: EBV could alter immune responses of T/NK cells to increase cancer risk, or altered T/NK responses at the time of EBV infection could be the critical factor. Alternatively, reduced Th1/Th17-type immune profiles after infection – along with reduced T regulatory cell responses – might skew some individuals toward autoimmunity, raising the risk for more severe autoimmune diseases, including atypical multiple sclerosis or even autoimmune-mediated epileptiform disorders. But at this early juncture this remains only speculation.”

Epstein-Barr Virus (EBV) brings up the age and exposure question. It’s much more difficult for the immune system to corral or ward off EBV if EBV is encountered for the first time at a later age (during or after adolescence). That difficulty shows up as the months long fight to beat EBV called infectious mononucleosis.

A meta-analysis of studies examining many environmental risk factors for multiple sclerosis (including vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers) found that only three were associated with an increased risk of coming down with MS. Two of those concerned EBV (having had infectious mononucleosis, IgG seropositivity to EBNA). (The last significant factor was smoking).

Could a later exposure to EBV which resulted in infectious mononucleosis be the straw, so to speak, that ultimately broke the camel’s back for some of the atypical patients?

Dr. Hornig agreed that a study parsing out the rates of infectious mononucleosis in ME/CFS could be helpful but said it was hard to know at this point if IM played a role. She said that the CII group was investigating EBV further:

 “Hard to know (if late exposure to EBV is involved)- we are looking for clues suggesting greater risk for autoantibody-mediated disease in EBV and other virally-exposed subsets of ME/CFS. We do know that females have higher risk for autoimmune disease, but the sex skew only begins after puberty (when females might have come down with IM [Infectious Mononucleosis]).”

Poor Networking

Not only was less immune activation present earlier in the atypical groups but a network analysis indicated a weaker immune network was present as well. These network analyses assess the “wiring” present in the complex immune system.

Immune mediators called cytokines (and other immune factors) form these networks when they communicate with each other to drive an effective immune response.  While a central immune network was found in the typical patients, no such network connection was found in the atypical group.  That suggested a less robust immune response was occurring.

Pro-inflammatory Markers Down

pathogen

A less than robust immune response to an infection could play a role in the atypical group.

Surprisingly, the atypical group’s spinal fluid had lower levels of two pro-inflammatory cytokines, IL17A and CXCL9.  Given the atypical group’s increased neurological and cognitive problems one would have expected the opposite.

That suggested that the atypical patients might be more than different in degree; they might be different in kind. The TH17 pathway that underlies many autoimmune and inflammatory diseases, and which the authors believes may be contributing to the typical ME/CFS group, doesn’t appear to be in play in the atypical group. In fact, the authors suggested the researchers vigorously pursue “alternate, nonimmune mechanisms of pathogenesis in more complex, atypical patients with ME/CFS.”

Dr. Hornig suggested genetics might play a role or that a different kind of immune response; one that was a bit too weak early on to knock off a pathogen, was another possibility.

“I think it may rather be the kind of immune response (inadequate inflammatory responses that might serve to contain an infectious agent upon first exposure, with skew towards autoimmunity or permissiveness to later uncontrolled growth of abnormal cells – i.e., neoplasia) and its timing (too little early on, with some limited immune escape at later time points, allowing for some inappropriate inflammatory type responses after the infectious agent has already had an opportunity to set destructive processes in motion – but too little and too late to contain or eradicate the pathogen).”

That could set up what Dr. Hornig called a “smoldering inflammatory process”.

Cause(s)

What might be causing the immune systems of the atypical group to act so differently early on? Dr. Hornig warned that it was essential that the study results be confirmed by a larger study but suggested that different triggers (unusual infections) or genetic vulnerabilities  (environmental susceptibility, immune response, autoimmunity genes) or even one’s age at exposure could play a role.

Results Suggest Atypical ME/CFS Patients Should Be Screened for Cancer and other Diseases

As with any single study the results need to be validated in studies by other labs using other patients to be validated. If they are, though, they could help doctors and patients. Dr. Peterson said:

 “Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes.”

Hornig and Lipkin suggested that atypical ME/CFS patients should be screened for cancer just as patients with paraneoplastic syndromes are. Paraneoplastic syndrome occurs when an immune response against cancer affects other parts of the body, often before a diagnosis of cancer is made.

How Common are Atypical Patients?

How many patients are “atypical”? In her answer to that question Mady Hornig called for more comprehensive studies to fully understand ME/CFS.

 “Though we know comorbidity rates in ME/CFS are thought to be high for quite a number of conditions (allergies, gastrointestinal problems), few studies have addressed this issue in a systematic manner.

It is rare to find physicians who specialize in this disorder, let alone follow the same individuals over time. Given the finding that prior to the development of these other serious comorbidities, all members of this subset met research diagnostic criteria for ME/CFS and would only later qualify as “atypical” based on subsequently developing comorbidities (over many years), we desperately need longitudinal studies that monitor for such issues.

The bottom line is that we don’t know what percentage of ME/CFS patients are “atypical”.”

It’s not clear what percentage of ME/CFS patients are atypical but they may  have already had a dramatic impact on ME/CFS research and treatment. Dr’s Fluge and Mella started the Rituximab saga in ME/CFS after noticing improvements in the fatigue, etc. of ME/CFS patients who’d come down with cancer; i.e. atypical patients.

Dr. Hornig has called the spinal fluid samples Dr. Peterson has collected over the years a “precious” resource, and she highlighted his persistence in collecting them over the years.

 “There also may be long-term cohorts at some ME/CFS clinical sites that might be available for closer examination, at least with respect to clinical patterns and disease/comorbidity trajectories. But most of these sites are unlikely to have cerebrospinal fluid samples (let alone plasma samples) banked in a repository for years!

The suggestion that biological pathways in the CNS already look different even before the onset of these comorbidities implies not only that screening and surveillance are likely to be important to ensure better long term care for individuals with ME/CFS, but also that treatment might need to be tailored differently in classical vs. atypical subsets.”

 Similar Issues Showing Up in Other Neurological Diseases

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Subsets are common in neurological diseases.

Gunnar Gottschalk, a co-author of the study and medical student is a former research manager for Simmaron Research Foundation. He’s been deeply immersed in ME/CFS research for several years and continues as a Trustee of the Foundation.  Gunnar noted that the neuroscience lab he is working in is studying similar issues in Parkinson’s, Alzheimer’s and other neurodegenerative diseases. It’s not that the same findings are present but that highly abnormal spinal fluid cytokine findings are showing up in all these diseases –  including ME/CFS.

Nor is this study’s general finding – that atypical patients can be differentiated from typical patients in ME/CFS – unusual in the neuroscience field.  Virtually every neurological disease, Gunnar said, appears to be studded with subsets. Different types of multiple sclerosis, for instance, have been identified using similar kinds of spinal fluid analyses.

Noting that developing animal models are critical to understand what’s happening in the brain, Gunnar said he wouldn’t be surprised at all if some animal models which have been developed at great cost for other diseases wouldn’t eventually be helpful in some ways for ME/CFS.

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Next Steps

This is not it for the spinal fluid and the atypical patients. Metabolomics and proteomics studies are next in Phase 2 of the study, which is being funded by Simmaron.  Gunnar noted that the cytokine studies can identify important pathways, but the metabolomics studies can provide more detailed results and he’s eager to see how they turn out.

Dr. Hornig has a long, long list of studies she’d love to do in ME/CFS. This is a disease, she feels, that is calling out for comprehensive studies. She wants to analyze blood, fecal and spinal fluid samples collected at the same time to assess what infection or environmental insult the patient is reacting to.

Comparing immune profiles in the blood and spinal fluid could, for instance, help tell her whether powerful immune cells are squeezing though the blood-brain barrier and wreaking havoc in the brain. Determining that immune cells from the periphery are in the brain would open an entirely new window on ME/CFS.

The gut is another area primed for research. Dr. Hornig pointed out that it’s clear that the bacterial communities in our gut shape our immune response. The TH17 profile found in some patients that tilts the immune system towards inflammation could derive from danger signals produced in the gut. Similarly the TH2 profile found in other patients that tilts them towards autoimmunity could come from the gut as well.

What Dr. Hornig wants is “system-biology” work that ties all these systems into a coherent whole. A gut level disturbance could, for instance, end up impacting virtually every system involved in ME/CFS – including the central nervous system.

“Further systems biology-type work will help us delineate how altered gut microbiota might translate into faulty signals – ranging from bacterial or human metabolites, including a range of immunity-modifying and neuroactive molecules, to immune molecules, to autonomic/vagal nerve axis effects – that then access the CNS (perhaps involving damage to the integrity of the blood-brain barrier to allow entrance of these aberrant signaling molecules) and disrupt brain function.”

In fact, Mady Hornig and Ian Lipkin do have most of the samples they need to begin this work. In what must have been one of the stranger NIH grant awards ever, however, the NIH funded the collection of an enormous amount of samples taken at four points over a year in 250 ME/CFS and healthy controls, but has not funded the analysis of these very same samples.

“In the more recent longitudinal NIH study we have no funding at all for laboratory studies, but have a unique banked set of well-characterized samples (oral, fecal and blood).” (bold added)

Having so many samples just sitting there is astonishing, and hopefully the second half of the study will get funded.

When I asked Dr. Hornig about funding the metabolomics and proteomics work she said that the metabolomics and proteomics assays had been run – but only for a subset of patients.  The CII, she said had funding:

 “Only for analysis of a subset of the Chronic Fatigue Initiative main study cohort samples (and this assay work is completed with analysis in progress) – not for the latest 125+ cases and 125+ controls based on the 1-year, NIH-funded study with 4 serial sample collections.

We don’t have any funding to follow up on candidates identified, including validation, quantitation and correlation with genetic, epigenetic and RNA-based assays.”

 A Foundational Approach To ME/CFS Proposed

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Large foundational studies are needed to take ME/CFS to the next level

Dr. Hornig went further, though, and called for a “foundational” approach to chronic fatigue syndrome (ME/CFS) that included national registries which would be able to tease out subsets and determine just what happens as people get ME/CFS.

“To support this sort of work on a larger scale, fundamental and foundational work is required. National registries of ME/CFS populations could be developed that would have the capacity to identify the range of preceding potential triggers to disease, to define comorbidities at the time of diagnosis, as well as to longitudinally track the new occurrence of comorbidities in ME/CFS populations over time.”

That is the kind of vision this field needs.  That is the kind of vision that should be able to excite NIH and other funders.

The Simmaron Research Foundation’s unique spinal fluid work with the CII has thus far helped to identify two potential subsets in ME/CFS.  Validating the atypical or “Peterson Subset” could lead to a new understanding of how ME/CFS works and open new treatment options for patients.  The SRF looks forward to further collaborations with the Center for Infection and Immunity and Mady Hornig and Ian Lipkin as it works to redefine ME/CFS biologically.

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Poll Note: The poll will only allow one option to be picked. One positive response suggests you may be an atypical patient. Keep in mind, though, that this is early research on subsets and further studies are needed to verify the findings.

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Tea-Time at Simmaron I: Mady Hornig on the “Peterson Subsets”, Immune Exhaustion and New Gut Findings In ME/CFS

The Simmaron Research Foundation is out to redefine ME/CFS scientifically.  In an recent event called A Simmaron Tea, collaborators talked with patients about their recent work to propel discovery in our disease. Part 1 of our summary will review Dr. Mady Hornig’s presentation, including some early results from Columbia’s ongoing gut studies. Part 2 will summarize Dr. Konstance Knox’s study of mosquito and tick-borne pathogens in ME/CFS patients. Stay tuned!

Simmaron has collaborated with Dr. Hornig on half a dozen studies unfolding the immuological anomalies in ME/CFS. A doctor-scientist by training, she is Associate Professor of Epidemiology and Director of Translational Research at Columbia University’s Mailman School of Public Health.Simmaron Research | Scientifically Redefining ME CFS | #ShakeTheCFSstigmaSimmaron’s collaborations with Columbia on spinal fluid studies mark our signature contribution to ME/CFS research. Simmaron is continuing this research by funding a second phase of this work to compare metabolomics and proteomics in ME/CFS and MS patients.

Mady Hornig

“We now know that the same changes to the immune system that we recently reported in the blood of people with ME/CFS with long-standing disease are also present in the central nervous system,” Dr. Hornig

In her presentation, Dr. Hornig first reviewed the recent finding from the Chronic Fatigue Initiative-funded study run by the Columbia team: massive immune up regulation in short duration ME/CFS patients and immune down regulation in longer duration ME/CFS patients.  The same immune factors, interestingly enough, that were upregulated early in the illness were squashed later in the illness. One key viral fighter called IFN-y that was hugely important in early ME/CFS but significantly down regulated in later ME/CFS pointed an arrow at a process called “immune exhaustion”.

Immune Exhaustion

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The blood and spinal fluid findings matched

The first cerebrospinal fluid study using Dr. Peterson’s carefully collated samples found a similar pattern of immune system down regulation. That study (supported by CFI and Evans Foundation) included only longer duration patients.  These two studies – the first to find similar issues in these two different compartments of the body – suggested that the immune system had taken a system wide punch to the gut.

What could cause this kind of immune exhaustion?  Dr. Hornig stated it’s usually associated with chronic infections. In a scenario reminiscent of the wired and tired problem in ME/CFS, the immune system gets revved up, stays revved up and ultimately crashes.

That nice concurrence between immune findings in the spinal fluid and in the blood was encouraging, and the group is digging deeper into those CSF samples. Thus far a factor called cortisol binding globulin (CBG) has popped up in protein analyses. This intriguing factor which facilitates the transport of cortisol in the blood, has shown up in chronic fatigue syndrome before and families with certain polymorphisms in their CBG genes have increased fatigue and low blood pressure.

The Peterson Subsets

Earlier, Dr. Hornig noted Dr. Peterson’s exceptional foresight at collecting cerebrospinal fluid samples over many years and his skill at characterizing them. Now she appeared almost dumbfounded at his ability to pluck out subsets in his patients. At Dr. Peterson’s urging, the Columbia team examined the cerebrospinal fluid of what he called “classical” ME/CFS patients and “complex atypical” patients. Dr. Peterson has been talking about the “classical” set of ME/CFS patients vs other types of patients for years, but this was the first time his intuition was put to the test.

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Finding subsets was crucial to the success of both studies

The classical patients typically present with infectious onset while ME/CFS in the atypical patients has been associated with post transfusion illness, cancers and other factors. No one before has suggested or attempted to determine if these patients differ biologically.

Dr. Peterson’s intuition that they would be different biologically proved to be correct. Columbia found dramatic differences in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. The researchers are taking a deeper look at the cerebrospinal fluid in these two types of patients.

The findings also demonstrates how vital it is to tease out subsets. Without breaking patients up into early and longer duration subsets the findings of the CFI’s big immune study would have been negative.  Similarly, without excluding Peterson’s subset of  atypical patients, the cerebral spinal fluid study findings would have been insignificant. Given the size, expense and prominence of the CFI blood study, in particular, the negative results would have provided a significant impetus for the field to move away from the immune system.

Instead, there is now great interest in immune alterations in ME/CFS. The inability to ferret out biologically important subsets has undoubtedly smothered potentially important findings in ME/CFS in the past. In a short period of time the CFI investigators and Dr. Peterson have added two factors ME/CFS researchers need to consider in their studies: duration of illness and classical vs non-classical patients.

This is an example of “translational medicine” – going from the bench (lab) to the bedside (clinic) and vice-versa – at its best. It can only occur when researchers interact closely with practitioners they trust and vice-versa.

The Gut Work

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Mady Hornig believes the gut may hold answers to ME/CFS. The preliminary gut results suggest she may be right.

Columbia’s Center for Infection and Immunity has  completed the testing of samples from 50 patients and 50 healthy controls started in the CFI study and extended in an NIH-funded study to analyze ME/CFS microbiome. They are completing analysis of the samples now.

They’re finding evidence of significant changes in the gut flora of ME/CFS patients vs healthy controls. For one, altered levels of butyrate producing bacteria have been found in the ME/CFS patients. Noting that similar differences have been found in autoimmune diseases, Dr. Hornig proposed that an autoimmune process may be fueling the symptoms in a subset of patients.

Another finding suggests substantial serotonin dysregulation may be present in ME/CFS. (Most of the serotonin in our body is found in our gut.) Dr. Hornig described serotonin as a major immune regulator. Thus far they’ve found that serotonin is more likely to be undetectable in shorter duration patients than longer duration patients, and those reduced serotonin levels are associated with increased immune activity including a very significant increase in IFN-Y – an important antiviral factor.

Tryptophan is metabolized to either serotonin or kynurenine.  If serotonin levels are low, the levels of kynurenine are likely high. Plentiful serotonin results in feelings of well-being, emotional resilience, and immune balance. High levels of kynurenine, on the other hand, have been associated with a host of neurological and neuropsychiatric disorders. Dr. Hornig has called the kynurenine pathway her favorite pathway because it’s been implicated in so many diseases.

The low serotonin findings in ME/CFS were apparently significant enough for Columbia to begin developing new tests to more accurately assess the presence of kynurenine metabolites. It appears that they’ve been successful in doing that, and we can expect more fine-tuned analyses of the role that pathway plays in ME/CFS.

In discussion afterward the presentation, Dr. Hornig said she was struggling a bit how to relay ideas of low resilience to stress in ME/CFS – some of which low serotonin levels could play a role in – without ruffling feathers.  She’s certainly not advocating the SNRI’s or other antidepressants in ME/CFS. In fact, she noted that she was sure ME/CFS patients were amongst the “treatment resistant depression” patients she’d seen when working as a psychiatrist early in her career.

The fix for the serotonin problem – if it is validated in a subset of ME/CFS patients – will clearly come from another direction. A recent review article suggested using the gut flora to affect serotonin-based brain disorders and that is probably the track Dr. Hornig will take. She said she is especially keen to look at the effects of nutraceuticals, probiotics and fecal transplants in ME/CFS.

Dr. Hornig is clearly intellectually excited by her work, but one thing that happened during her presentation indicated her strong emotional connection to it as well.  The presentation of a small quilt to her from ME/CFS patients strongly affected her and left her having to momentarily gather herself emotionally.  It was a surprisingly moving moment.

Dr. Hornig sounded confident about the direction of their research and stated that they were veSimmaron Research | Give | Donate | Scientifically Redefining ME/CFSry much looking forward to what the next few years will bring.  She said she was cautiously optimistic that the IOM and P2P reports, the positive immune study, plus the signs that the National Institute of Neurological Disorders and Stroke (NINDS) may be interested in taking ME/CFS on, indicate that a turnaround for ME/CFS funding is in store.

Help Simmaron continue to fund this pivotal work, as we seek to deepen immune findings in ME/CFS and turn them into potential treatments.