All posts in Immune System

Large NK Cell Study Points to Autoimmunity and Inflammation in Chronic Fatigue Syndrome (ME/CFS)

The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. Rivas et. Al. 2018

Problems with natural killer (NK) cell functioning have been like an anchor in the storm for immunologists interested in chronic fatigue syndrome (ME/CFS). While other immune results like cytokines have flipped and flopped all over the place, the NK cytotoxic results have been solid. Almost every study has found that when given the chance to kill infected cells, the NK cells in ME/CFS patients poop out.  (The studies which have not found differences in NK cell functioning have tended not to use whole blood or used older samples – suggesting that something in the blood could be impairing NK cell functioning in ME/CFS.)

Dr. Daniel Peterson, Sierra Internal Medicine and Simmaron Scientific Advisor

The most extensive study – a year-long 2012 study involving Dr. Peterson and Griffith University in Australia – found reduced natural killer cell functioning at all time points. (Peterson has a long history of interest in natural killer cells; he was a co-author of the first study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS).)

NK cells are important because they maintain the lines of our initial immune defense, holding the fort, so to speak, until the big guns – the T and B cells- wipe out the infection. – They also regulate the immune response.

Normally our cells signal that they are infected by displaying peptide fragments from the pathogen (using MHC Class 1 molecules) on their surface. NK cells then hunt out and destroy these infected cells. However, some pathogens have learned how to prevent the cells they’ve infected from displaying these peptide fragments.

If NK cells and other parts of the innate immune response can’t hold back the invaders, the pathogens may invade more deeply into the body, potentially causing more problems before the adaptive immune response (T and B-cells) can kick in.

innate immune response

Mast cells, complement, phagocytic cells and natural killer cells man the early or innate immune response

A deficient early response to pathogens would then very likely translate into more symptoms. We don’t know when the problems with NK cell killing got started in ME/CFS, but if they were in place prior to the illness or occurred early in the illness they could have played a role in the inception of ME/CFS as people who have more trouble fighting off a pathogen; i.e. people with more severe symptoms, are more likely to come down with ME/CFS.

Once ME/CFS has begun, the inhibited NIK killing response could mean more trouble removing tumor and infected cells – particularly herpes virus infected cells- as people deficient in NK cells  have trouble fighting off herpes viruses.

NK cells, then, are vitally important, but attempts to identify issues other than cytotoxic killing abilities have been less successful. NK cells come in different types (cytotoxic and regulatory) and the balance of these subpopulations is important. Some studies have found differences in these subpopulations in ME/CFS and some have not.

Many of those studies, however, have been small and used less than stringent criteria for defining ME/CFS. A Spanish group decided to rectify those problems with a more definitive study which examined NK cell populations in a larger study (n=149) with patients who met the Canadian Consensus Criteria for ME/CFS. In order to ensure they captured all factors in the blood that might be whacking NK cells, they used whole blood and analyzed it within 6 hours of collection.

Then they tried to reverse engineer their results to see if a diagnostic test could be developed which simply charted which kinds of NK cells a person had. That was pretty good, but then they went further and asked if people who were worse off had different subpopulations of NK cells or more evidence of herpes virus reactivations (EBV, HMCV).

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Jose Luis Rivas,1,* Teresa Palencia,1 Guerau Fernández,2 and Milagros García1,3 Front Immunol. 2018; 9: 1028.Published online 2018 May 9. doi:  10.3389/fimmu.2018.01028

This larger, fresher (quick analysis of blood), stricter (CCC patients only) and more comprehensive study found differences where others had not – and plenty of them.  This group validated – with a high degree of certainty (p = 0.0075) – previous findings of  an increased subpopulation of NK cells (NK CD56++(high)) which, get this, excrete more cytokines (particularly IFN-y), possibly causing more symptoms, but which have low cytotoxic activity.  Because these cells have unusually long life spans and pump out cytokines that cause more T-cell proliferation, higher numbers of them could contribute to autoimmunity and inflammation.

These cells were particularly high in the group of patients whose illness began without evidence of an infection. The Spanish group suggested that activation of the stress response via the HPA axis and raised levels of catecholamines such as norepinephrine (adrenaline) could have triggered the expansion of this potentially autoimmune affecting natural killer cell subset.

No differences were found, however, in the levels of several receptors (NKp46, NKp30, NKp44) that have been found elevated in some autoimmune/inflammatory conditions (Sjogren’s Syndrome, Crohn’s disease) or reduced in chronic infections (HIV, tuberculosis, influenza, etc.).

CD 69

Increased levels of the CD 69 marker suggested autoimmunity may be present in ME/CFS

Reduced levels of a receptor (NKG2C) were very common (p<0.0001) in ME/CFS. When this receptor, which is only found in NK cells, is activated by the presence of virally infected cells, it triggers an expansion of NK cells. Not surprisingly, NK cells become dotted with this receptor in people with chronic herpesvirus and other infections (HCMV, EBV) but ME/CFS patients’ NK cells had consistently lower levels of this receptor than did the healthy controls.  The authors didn’t speculate why this occurred, but it could involve lower levels of infection in ME/CFS – something Ron Davis is finding in his severely ill cohort – or a problem responding to infections that are present.

That second possibility was buttressed by an inverse correlation found between a marker of infection (CD 57+) and the lower expression of a marker (NKp46) which is often reduced in herpesvirus infections. The authors suggested that the scenario found in ME/CFS (increased cd57+, lower NKp46, high NKG2C) could reflect HCMV (cytomegalovirus) reactivation.

Watch Natural Killer T-cells (red) Swallow Up Antigen Presenting Dendritic Cells (green)

 

Increased levels of the CD69 marker (p= 0.011) provided another suggestion that ME/CFS may be an autoimmune/inflammatory disease. This important marker, which is found on many immune cells, stimulates NK cell cytotoxic activity. More importantly, CD69 has been described as a master regulator for autoimmunity in rheumatoid arthritis (RA) through its upregulation of TGF-B – one of the very few cytokines that has usually been found increased in ME/CFS.

A “descent” in T regulatory cells similar to that found in autoimmune conditions such as lupus and RA was also found. Finally, an inverted Th17/T regulatory cell ratio, which is also found in autoimmune conditions like lupus, wrapped up the autoimmune connections found in this study.

Using a mathematical classification model, the group was able to correctly diagnose 70% of ME/CFS patients and healthy controls simply by using the findings from this in depth study of natural killer cell populations.

Conclusions

This large Spanish study of NK cell subpopulations found numerous irregularities in NK cell types in ME/CFS, several of which pointed to issues with autoimmunity and/or inflammation. As in other studies, this study indicates that larger is indeed better when it comes to studying ME/CFS.

The study validated prior findings of an unusually large set of NK cells which produce more cytokines – conceivably causing more symptoms and immune activation – but which are less effective at killing infected cells.  That finding seemed to jive with a picture of highly symptomatic ME/CFS patients who may have trouble fighting off infections.

While no differences were found in the levels of receptors which can be elevated in autoimmune conditions, several other findings suggested that NK cells may be fighting off herpesvirus infections or may be involved in autoimmune/inflammatory processes in ME/CFS.

Finally, using just NK cell subpopulation data, the authors were able to correctly identify 70% of patients and healthy controls, indicating that significant NK cell differences exist. All told, the study identified several natural killer irregularities that could participate in autoimmunity and dysregulate other parts of the immune system.


Montreal ME/CFS II: Stopping PEM, the Antibody Subset and Unutmaz’s Big Surprise

The second part of a several part series on the Montreal ME/CFS conference focuses on the immune system.

Part 1: The Montreal ME/CFS Conference: Metabolism and Exercise can be viewed here.

Dr. Nancy Klimas: From Biomarkers to Modeling and Clinical Trials; GWS and ME/CFS

Years of work appear to be coming to fruition for Dr. Klimas. Her ability to hook into GWS funding has made a huge difference in her ability to test out her modeling protocols.  It’s remarkable to see the Dept of Defense lay down $40 million per year for the vets affected during the Gulf War 27 years ago, while ME/CFS gets so little. The vets undoubtedly deserve it and they deserve more – many lives were shredded as a result of the war and they’ve fought for years to get recognition. However, the disconnect between the way the feds have treated GWI and ME/CFS – a disease which affects far more people – is startling.  The Dept of Defense hasn’t done great by its vets, but it’s been much more responsive to them than the feds have been to ME/CFS and fibromyalgia.

Nancy Klimas

Years of work appear to be coming to fruition for Dr. Klimas

Dr. Klimas noted that the more we look, the more immune abnormalities are being found.  Cytokines may not tell us what is causing ME/CFS, but they sure could help us find drugs to combat it.  Klimas is comparing the immune signatures she’s seeing in ME/CFS with those of other diseases and then checking out what’s working in those diseases. The good news is that immune-affecting drugs are big business now, with more and more coming on the market. If ME/CFS is, at its heart, an immune disorder, or if the immune system plays a large role – as many think it does – drugs developed for other diseases may be able to help.

Dr. Klimas and her researchers have been asserting for years that ME/CFS patients are stuck in a kind of suboptimal, self-reinforcing homeostatic space; i.e. their systems have been rewired to produce a new normal.

That idea doesn’t seem to be all that far from Naviaux’s belief that people with ME/CFS are stuck in a Dauer state or Dr. Cheney’s report that while he could push patients towards health, something would pull them back.  Both Klimas and Naviaux believe a series of structured moves will be needed to move the system back to normal. Neither believes it’s easy; Klimas says real “force” will be needed to move the system back into health.

Klimas should know – she’s been intensively charting how ME/CFS patients’ systems go off the rails during exercise for several years now. She’s measured every cytokine, neuropeptide, etc. she can at 8 timepoints before, during and after exercise in 50 women with ME/CFS, 25 women with FM, 50 men with ME/CFS and 50 men with GWI.

She’s gathered a vast amount of data and that data is telling her that ME/CFS patients’ immune systems basically go nuts during the first 15 minutes of exercise.  Four hours later, oxidative stress kicks in and the autonomic nervous and endocrine systems and metabolism get hit — but it’s the immune system that kicks everything off.

The big surprise is how different chronic fatigue syndrome (ME/CFS) is from Gulf War Illness. The metabolism gets hit hard in ME/CFS – everything gets shut down – but in GWI, all the pathways are ramped up. They’re two completely different illnesses which from the outside look exactly the same.

Dr. Klimas and her team have been running sophisticated modeling techniques on supercomputers to figure out how to get our systems back to normal. Initially, they ran into trouble with women who, no surprise, have much more complex systems than men. Back to the drawing board they went. In the end, Dr. Klimas’s team was able to create a virtual clinical trial in GWS. First, they brought down brain inflammation using etanercept, and then readjusted the HPA axis with a glucocorticoid receptor blocker, mifeprestone.

It worked on the computer – their virtual GWS patient returned to health system – but the big test came with their Gulf War Syndrome mouse model.  When the drug combo was able to return the GWS mouse to health they really knew they were onto something. An open label phase I trial in GWS is under way as we speak.

supercomputers ME/CFS

Her team has used supercomputers to create virtual clinical trials

Dr. Klimas noted that the $30 million the DOD is providing for GWI has made a big difference where the rubber meets the road in medicine – in ten clinical trials that are underway. That’s in a disease that effects fewer people than ME/CFS but which receives federal funding for clinical trials.  That’s not true for chronic fatigue syndrome (ME/CFS) – federal funding for clinical trials is pretty much blocked.

Researchers can apply for clinical trial funding at NINDS and other institutes, but ME/CFS doesn’t have a chance against diseases like Parkinson’s and Alzheimer’s. The big issue is that the program announcement for ME/CFS – which lists subjects researchers can apply to study – doesn’t allow them to submit clinical trials proposals.

Dr. Koroshetz’s promise last year to get that language embedded into the ME/CFS PA hasn’t paid off yet. Getting that wording embedded into the PA for ME/CFS could open up funding for clinical trials. That would be a big step forward.

Dr. Klimas doesn’t have a mouse model for ME/CFS but she’s been doing the same computer modeling she used in GWS on ME/CFS. It’s clear that nobody at this point understands more about what happens during exercise in ME/CFS than Dr. Klimas. Nobody has been able to translate mountains of exercise data into virtual clinical trials. Nobody has proposed a staggered two-drug approach to ME/CFS, and nobody probably has a better shot at stopping PEM than her.  This is new stuff not just for us but for the medical field in general. Let’s hope it works out.

The GWS trial is underway and she hopes to get her chance at halting the PEM in its tracks in ME/CFS in a small trial later this year. Getting funding, of course, will be crucial.

ME/CFS rather suddenly has several drug/drug trial possibilities: they include Cortene, Dr. Klimas’s drug combo, immunoadsorption (see below), Fluge and Mella’s Norwegian cyclophosphamide trial,  Ampligen and Dr. Kaiser’s Synergy drug-nutrient combination – and, of course, Rituximab is still surely in the picture for a subset of patients.

Carmen Scheibenbogen

Scheibenbogen is a mover and shaker. She’s published six papers on ME/CFS in the past three years, is a leader in the Euromene Group, has been talking to pharmaceutical companies about drugs, and is organizing a fatigue conference in Germany to get some good networking going.

Rowe - scheibenbogen - ME/CFS

Dr. Rowe called Dr. Scheibenbogen’s antibody findings one of the most exciting ME/CFS research findings in years.

Peter Rowe called her recent autoantibody papers one of the most exciting recent developments in the field. Scheibenbogen, interestingly, got the idea to do those studies from similar recent findings in POTS (postural orthostatic tachycardia syndrome).

Scheibenbogen rattled off some of the commonalities between autoimmune diseases and ME/CFS. Both predominantly affect women, both are often triggered by an infection and she’s found a high family history of autoimmunity in ME/CFS.  Plus, Epstein-Barr virus – a common trigger in chronic fatigue syndrome (ME/CFS) – invades B-cells which are the main drivers of autoimmunity. The difficulty ME/CFS patients and others have fighting off the virus when exposed to it later in life apparently gives the immune system plenty of opportunity to make a mistake and begin attacking our own tissues.

Check out a recent breakthrough in EBV-associated autoimmunity

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

Rituximab is used to treat autoimmune diseases. The Rituximab ME/CFS trial’s main endpoint failed but Scheibenbogen asserted that we shouldn’t count Rituximab out at all. She believes, and she would know, because she’s studied Rituximab patients, that Rituximab will be shown to be effective in a subset of patients.  An effective treatment in a subset of ME/CFS patients would be a big deal – particularly for those patients.

Scheibenbogen found increased levels of antibodies in about 40% of ME/CFS patients, and Bergquist’s study that is currently underway thankfully had similar results. At least right now it appears that the 40% figure is solid, but the search for antibodies in ME/CFS is not over. When I asked Scheibenbogen if other antibodies might be involved, she said, yes, other antibodies probably will apply. If that’s so, that 40% number could go up. Scheibenbogen noted that the B2 and muscarinic antibodies that have been showing up in ME/CFS are part of a larger network.

Interestingly, these are not autoantibodies; they’re natural antibodies which affect breathing, the circulation and the gut. Their high levels in ME/CFS appear to be throwing those systems off.

Immunoadsorption

Immunoadsorption is another possible immune treatment for chronic fatigue syndrome (ME/CFS). Immunoadsorption, which is similar to, but more effective than plasmaphoresis, removes IgG autoantibodies from the blood. It’s an expensive treatment – about $20,000.

Like Rituximab it will probably be effective in a subset of patients. Scheibenbogen’s small immunoadsorption trial of ME/CFS patients with specific autoantibodies found that the treatment did what it was supposed to do – it significantly reduced antibody levels for at least six months.

Symptoms improved in most patients and some patients completely recovered. Three are still in remission a year after the treatment ended. One person completely recovered for 6-7 weeks but then relapsed. After she relapsed, she could hardly walk again. The trial suggested that Scheibenbogen is on the right track with her autoimmune studies. The fact that POTS is so prevalent in ME/CFS and has similar autoantibody issues suggests that the outcome is not such a surprise.

The trial was small and carefully curated to those with high antibody levels but most patients improved and some recovered

The trial was small and carefully curated to those with high antibody levels but most patients improved and some recovered

A follow-up study is beginning. If that works out, Scheibenbogen hopes for a big trial that will settle the issue definitively.  In a good sign, she reported that the company that produces the immunoadsorption treatment (not available in the U.S.) is quite interested in ME/CFS.

(Even if the treatment is not available in the U.S., a successful trial could do a couple of things: it could prompt the company to make the treatment available in the U.S., and it would surely enhance autoimmunity research. We’ll see what happens, but if we can come up with several treatments – each of which is effective in a subset of patients – we’ll start to whittle the disease down.)

As she left for the airport, Scheibenbogen said she hopes that in the next five years ways to diagnose and treat ME/CFS will be found. Let it be so…

Guidelines to Biomarker Produced

Euromene, the new ME/CFS European research group Scheibenbogen is working with, recently laid out a step-by-step pathway to develop a biomarker. She noted that we have lots of interesting findings, but none that are unique to ME/CFS. Plus, the findings we do have overlap too much with healthy controls.

In short, we haven’t found that key signature – that key physiological mark – which says a person has ME/CFS. (That may not be a surprise: until we find the core of ME/CFS, we may not be able to find a unique biomarker). Scheibenbogen did wonder, however, given Maureen Hanson’s recent inability to find subsets in her metabolomic data, if the biomarker for ME/CFS will be metabolic in nature.

 

Unutmaz’s Big Surprise

Ron Davis has noted things often don’t work out the way researchers expect them to. Apparently, Derya Unutmaz feels the same way.  Unutmaz got a T-cell result that pointed straight at the gut and then was pleasantly shocked when a look at the gut confirmed his findings.  He was expecting a few more twists and turns from the body! It’s not usually so easy.

He noted that over the past decade a tremendous amount of work has been done on the effects the gut microbiome (gut bacteria) have on the immune system. It’s now clear that a shift toward more inflammatory bacteria in the gut can result in inflammation in other parts of the body. In fact, Unutmaz reported that just about every disease is associated with a change in gut bacteria.  The bacteria play such a vital role that oncologists can even determine how effectively patients will respond to immunotherapies by assessing the kind of bacteria they carry in their guts.

That makes sense for ME/CFS, since every gut bacteria study has thus far found substantial alterations in the bacteria in ME/CFS patients’ guts.

Unutmaz is a T-cell guy. He knows that bacterial metabolic by-products trigger unusual T-cells called  MAIT T-cells (Mucosal associated invariant T cells) to get into action. Once these cells, which are found in our gut lining, liver, lungs, etc., come across those metabolites, they secrete pro-inflammatory cytokines. Those cytokines turn monocyte cells into hairy monsters called macrophages which then gobble up the bacterial-infected cells.

MAIT cells, then, play a key role in turning on our immune response to the bad bacteria that can live in our guts. They apparently lurk in the gut lining as a kind of last line of defense against those bacteria getting into our blood stream and invading the rest of the body.

gut bacteria chronic fatigue

Unutmaz’s findings suggested that T-cells in the ME/CFS patients’ guts had been repeatedly exposed to bad bacteria

Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients – suggesting a plethora of bad bacteria was present. In true ME/CFS fashion, Unutmaz also found that ME/CFS patients’ MAIT cells were activated — but “punked out” at the same time. (A wired and tired immune cell?).  Seemingly exhausted by the continual stimulation, they (like their natural killer cell cousins) had problems killing infected cells. That hearkened back to the Lipkin/Hornig immune finding of activated immune systems in early-duration ME/CFS patients and depleted immune systems in longer- duration patients.

Unutmaz is now trying to identify which bacteria are tweaking ME/CFS patients’ MAIT T-cells so much as to possibly burn them out. If he’s successful, he may have found a target that could quiet down a possibly overworked and burnt-out immune system and allow it to rejuvenate.

Are Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Immune Exhaustion Disorders?

Part 1: The Montreal ME/CFS Conference: Metabolism and Exercise

 

Did a Multiple Sclerosis Study Give Us Clues About ME/CFS and Fibromyalgia?

Why should a blog focused on chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) be interested in multiple sclerosis? Because some distinct similarities exist between the three diseases, and when diseases like ME/CFS and FM aren’t getting much research, sometimes it pays to pay attention to diseases that are. You never know what insights might open up.

MS and ME/CFS

A recent study indicated that ME/CFS was more functionally disabling than multiple sclerosis

For the record, while multiple sclerosis is not as disabling as ME/CFS (yes – studies indicate that ME/CFS is more disabling than MS), MS is considered one of the most fatiguing diseases known.  (Dr. Light’s study actually found more fatigue in MS but much less post-exertional malaise ME/CFS.)

A “Fatigue” Disorder No More? – What Multiple Sclerosis Taught Us About Fatigue and Chronic Fatigue Syndrome

Additionally, MS like ME/CFS and FM, mostly strikes women in mid-life. Plus, having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and one suspects, FM as well.  Infections often trigger relapses in both MS and ME/CFS. Pregnancy also often brings a respite for women with either MS or ME/CFS (often unfortunately followed by a relapse.) Central nervous system involvement is present in all three diseases. In fact, Simmaron’s spinal fluid study found similar levels of immune dysregulation in ME/CFS and multiple sclerosis.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

A New Multiple Sclerosis Study Breaks Through

Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1520-E1529. doi: 10.1073/pnas.1710401115. Epub 2018 Jan 29.Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility. Russi AE1, Ebel ME1, Yang Y1, Brown MA2.

A new MS study highlights a vital aspect of medical research – an animal model – that both chronic fatigue syndrome and fibromyalgia lack. It illuminates how researchers can use animal models to crack complex medical mysteries.  Tantalizing leads are present in both FM and ME/CFS but no one has been able to meld them into a bonafide breakthrough. That appears to have happened in MS.

Let’s see what happens in a well-studied, well-funded disease. As a bonus we’ll see that the hopeful breakthrough in MS could even have relevance to ME/CFS and FM.

One of the huge questions facing ME/CFS, fibromyalgia, MS and many autoimmune diseases is why so many more women than men get ill. Women don’t just get more autoimmune diseases, they tend to get them earlier than men and tend to have more severe cases.  No one knows why but researchers have been scratching around a possible answer for at least a decade.

The gender divide in MS has been well explored. The fact that puberty sparks an increase in MS incidence in females suggests a strong hormonal component is present.  A 2015 review agreed that sex hormones probably play a major role. Another noted that the autoimmune component of MS is greatly increased in women.

A Serendipitous Mistake Sparks a Major Finding

mouse animal study

A mistake in differentiating male from female mice led to a major discovery.

As so often happens in research, a serendipitous mistake sparked this discovery.  It began when a Northwestern University graduate student accidentally used a male mouse instead of a female mouse in an experiment. (Female mice are apparently hard to distinguish from male mice.) The researchers were using female mice to find genetic mutations that could help prevent the progression of MS – a female dominated disease.

When they ran the experiment they found, to their great surprise, that the genetic mutation that was protective in female mice actually made things worse for the male mice. (Talk about a gender divide.) Digging deeper, the team found that the genetic mutation in male mice blocked the activity of immune cells (ILC2) that are protective against multiple sclerosis in female mice. These cells halt the production of TH17 T-cells that initiate the attack on the myelin sheaths of neurons in MS.

Mast Cells Make Good

Mast cells are usually associated with allergic responses and in ME/CFS/FM with a condition called mast cell activation syndrome (MCAS) but this study revealed that mast cells can have a protective side as well.

Testosterone

A male hormone, testosterone, then reared its head.  In men testosterone triggers mast cells to produce a substance called IL-33 which stops the production of the TH17 cells in their tracks.  In fact, when the Northwestern University researchers removed the mast cells from the male mice their neurons came under attack and they developed mouse MS.  In the presence of testosterone, then, mast cells are a very nice thing to have.

testosteron

Testosterone levels could possibly could help explain the gender divide in MS as well as ME/CFS and FM.

Female mice, which have seven to eight times less testosterone than male mice, don’t produce enough testosterone to induce their mast cells to produce IL-33. Instead, female mast cells produce cytokines which increase inflammation and the TH17 T-cells that have been fingered in MS.

Testosterone has been on MS researchers’ radar for quite some time. A recent review of hormonal related changes in MS asserted that there is “compelling evidence that estrogen, progesterone, and testosterone control MS pathology by influencing immune responses and by contributing to repair mechanisms in the nervous system”.

Testosterone levels that drop as men age track with an increased incidence of MS in later life. (Interestingly the men who do get MS tend to have a tougher time with it than women.) Lower testosterone levels in men with multiple sclerosis are also associated with greater disability.  Some similar findings have been found in women. Women with MS tend to have lower testosterone levels, and increased lesions were associated with reduced testosterone levels in one study.

A very small clinical trial suggested testosterone supplementation might be able to increase white matter volume in the brains of men with MS.  If that finding is validated in larger studies, testosterone might be the first substance found that can reverse some of nervous system damage found in MS.

Testosterone, ME/CFS and FM

Testosterone levels could possibly could help explain the gender divide in MS as well as ME/CFS and FM.

A few studies have implicated testosterone in two other gender-imbalanced diseases – chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).

Two studies have found low levels of testosterone in fibromyalgia, and testosterone levels have strongly been linked to pain sensitivity in animal models. One recent study suggested that lower levels of testosterone in combination with other factors was associated with increased rates of depression and poorer sexual functioning in FM. Recently, Jarred Younger’s small “good-day, bad-day” FM study found that lower levels of two hormones, testosterone and progesterone, were associated with more severe FM symptoms.

Fibromyalgia – the Testosterone Connection

Despite concerns about the use of testosterone in women, White found that a 28 day course of testosterone gel reduced pain significantly in women with FM. (More about that later.)

In ME/CFS Broderick’s modeling efforts suggest that testosterone in men is protective.  Plus the high rate of gynecological issues in ME/CFS and fibromyalgia suggest that sex hormones are involved in ME/CFS.

High Rates of Gynecological Disorders Implicated in Chronic Fatigue Syndrome and Fibromyalgia

Sex, Autoimmunity and Chronic Fatigue Syndrome … or Why More Women Than Men Get ME/CFS

Testosterone and Autoimmunity

No one knows if ME/CFS and FM are autoimmune diseases, but both could be and the link could have something to do with testosterone. The evidence that testosterone is protective against some autoimmune diseases is building.

Adding the gut contents of male mice to female mice (another mouse model) reduced their risk of type I diabetes – an autoimmune disease. Interestingly, the protective element again appeared to be testosterone, the levels of which were highly influenced by the composition of the mice gut flora.

Declining testosterone levels in men as they age increases their risk for rheumatoid arthritis. Declining testosterone levels may also be responsible for the gender parity seen in RA by age 75, and could explain why men tend to get multiple sclerosis at a later age than women. Low androgen levels in both men and women also appear to put them at risk for autoimmune disorders.

The gender divide extends to opioid use. Regular opioid use suppresses testosterone in men but not in women.

A TH17 Connection

ME/CFS may share another connection with multiple sclerosis – a deranged TH17 response. TH17 T-cells defend against extracellular pathogens and have been found to play a significant role in the development of inflammatory and autoimmune disorders. TH17 cells appear to help initiate attack on the neuronal sheaths in MS.

Several studies from Dr. Klimas’s group suggest a TH17 associated process may be in play in ME/CFS.  Exercise provoked a Th17 response  in both ME/CFS and Gulf War Syndrome patients.  Broderick’s modeling effort found that as few as five cytokines associated with TH17 activation could identify approximately 80% of ME/CFS patients with an infectious trigger. TH17 cytokines showed up again prominently in Broderick’s network analysis study which found they functioned as “preprogrammed immune component”.

Treatment

The question now is how induce a testosterone-like response in women without actually using testosterone. Drug studies suggest that testosterone can be helpful in MS but the study authors stated that women can’t take much of it without becoming masculinized and experiencing other significant side effects.

Instead this new MS study’s importance lies in the discovery of a key cytokine (IL-33) that can apparently turn off the destructive nerve processes in MS and even restore the nerves. If researchers can develop a way to promote IL-33 activity without using testosterone in women, they may have gotten a handle not just on MS but possibly on other gender imbalanced autoimmune diseases as well.

A New Approach to Autoimmunity?

The authors were quick to suggest that the findings may apply to other autoimmune diseases as well and could ultimately signal an entirely new approach to them. That’s welcome news given the harsh side effects of many of the immune suppressants used in autoimmune diseases.

“This suggests a mechanism for the reduced incidence of multiple sclerosis and other autoimmune diseases in males compared to females. These findings could lead to an entirely new kind of therapy for MS, which we greatly need.” Melissa Brown, PhD.

Perhaps it will lead to new direction in research for ME/CFS or FM.

NEID Disease? Study Suggests Neuro, Endocrine and Immune Systems Work Together to Produce ME/CFS

Bruun Wyller continues to surprise. When last heard from this erstwhile cognitive behavioral therapy (CBT) proponent asserted that more research into Epstein-Barr virus in chronic fatigue syndrome (ME/CFS) was needed. Now he’s looking at the interaction between the immune and endocrine systems.

The Evolution of a Chronic Fatigue Syndrome (ME/CFS) Researcher? CBT Proponent Calls for More Herpesvirus Research

Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome Vegard Bruun Wyller1,2*, Chinh Bkrong Nguyen1, Judith Anita Ludviksen3,4 and Tom Eirik Mollnes. J Transl Med (2017) 15:245 https://doi.org/10.1186/s12967-017-1350-

Wyller begins his new study reporting that systemic inflammation is probably present and B-cell functioning is impaired (if modestly) in ME/CFS, but that the picture regarding cytokines is muddier. A meta-analysis of 38 ME/CFS cytokine studies examining 77 cytokines found only one standout – a cytokine called TGF-B. It was consistently elevated in 2/3rds of the studies.

cytokines chronic fatigue syndrome

Only one cytokine has more or less consistently shown up elevated in ME/CFS studies – TGF-B

Given its unusual and consistent appearance in cytokine study results, why TGF-B has gotten so little attention in ME/CFS is unclear. The fact that it’s kind of a weird cytokine probably doesn’t help. Secreted by macrophages and some other immune cells, TGF-B can function as both an anti and pro-inflammatory cytokine depending on the situation it’s in.

It’s three forms are involved in a multitude of regulatory processes involving inflammation and immunity.  It does more than participate in the immune system; TGF-B also affects or is affected by the two stress response systems in our bodies – the HPA axis and autonomic nervous system. All that makes TGF-B a complex character indeed.

Take our two stress response systems. During stressful situations increased TGF-B levels appear to be associated with increased levels of cortisol – the main stress hormone of the HPA axis.  An ME/CFS study examining the gene expression of immune cells found an abnormally high expression of genes that interact with the HPA axis and autonomic nervous system. That suggested that a significant immune-hormone component is present. Indeed, ME/CFS has long been characterized as a neuroendocrineimmune (NEID) – a disease that effects all three systems.

In this study Wyller, a Norwegian researcher, again used his own broad definition of ME/CFS to find patients, but this time he did post hoc analyses using the Fukuda and Canadian Consensus criteria to determine if different definitions of ME/CFS made a difference – they didn’t). As always, Wyller studied adolescents – a lot of them (n=120) and 68 controls to produce a very nice sized study. The data analysis took a long time; the data itself was collected from 2010-2012.

TGF-B actually comes in three forms ((TGF‑β1, TGF‑β2 and TGF‑β3). For the first time ever in ME/CFS Wyller tested for all three forms of TGF-B, as well as norepinephrine, epinephrine and cortisol (urine) and c-reactive protein (serum).   He also assessed heart rate variability, and in 29 patients examined their whole blood gene expression.  Questionnaires assessing fatigue, inflammatory symptoms, post-exertional malaise, sleep, mood and anxiety were also given.

Results

Wyller expected TGF-B levels to be higher in his adolescent ME/CFS patients, but to his surprise even using the CCC and Fukuda criterias, they were not. Nor was TGF-B associated with any clinical markers such as fatigue, PEM, sleep problems, etc.

cortisol

Wyller suggests an unusual neuroimmune connection involving TGF-beta and stress hormones such as cortisol (pictured) may be present

The study was looking like a bust until Wyller dug a little deeper. It turned out that TGF-B levels were associated with increased levels of the stress hormones cortisol, norepinephrine and epinephrine in the ME/CFS patients but not in the healthy controls.

An unusual immune-endocrine interaction was occurring in ME/CFS patients that was not found in the healthy controls. For some reason, TGF-B  levels rose in conjuction with stress hormones in the ME/CFS patients but not in the healthy controls.  All three TGF-B isoform displayed this association.

Plus that association also correlated with symptom severity. Wyller found that the TGF-B-cortisol-autonomic nervous system correlation was strongest in the most fatigued ME/CFS patients.  Less fatigued ME/CFS patients, on the other hand, had much less of this association.

Once again, context appeared to be king in the ME/CFS patients. The levels of TGF-B didn’t matter but the network they were embedded in did. A similar scenario showed up in the huge cytokine study conducted by Dr. Montoya and Mark Davis of Stanford. That study, like Wyller’s, didn’t find high levels of cytokines, but it did find that even normal cytokine levels affected symptoms. That suggested some sort of immune hypersensitivity, perhaps associated with some unusual network functioning, was present.

Now Wyller apparently finds an immune and autonomic nervous sensitivity to TGF-B. It’s not the cytokine levels themselves but the effect they have on stress hormones.  Indeed, Wyller suggested that the primary disease mechanism in ME/CFS is not altered immune production but altered immune control. Somehow the immune system is affecting other systems in unusual ways.

That’s an intriguing idea given what we’ll shortly see from Dr. Klimas, whose intense testing during exercise suggests that exercise induced immune activity trips off autonomic nervous system problems in ME/CFS. Gordon Broderick’s network studies suggest that cytokine levels don’t need to be high to have untoward effects on ME/CFS patients – they simply have to be embedded in an unusual immune network.

Wyller - neuro-endocrine-immune disease

Wyller believes a complex neuro-endocrine-immune interaction may be contributing to the fatigue and possibly the EBV issues in ME/CFS.

Dr. Klimas will be trying in a series of small studies to move those systems back to normal this year. (More on that later.)

Wyller’s findings suggest that his “sustained arousal” hypothesis may be correct and that the “sustained arousal” he believes is present in ME/CFS is being triggered by the immune system. His small gene expression study possibly bares this out. Wyller warned about reading too much into the gene expression analysis because of the small sample size (n=29). The analysis found, though, that the TGF-B3 isoform was negatively associated with reduced expression of two B-cell genes (TNFRSF13C and CXCR5).

Wyller suggested that TGF-B3 may be altering the effect that cortisol – the master immune regulator – has on B-cell genes in ME/CFS.  If TGF-B and cortisol combine to smack B-cell genes in ME/CFS, Wyller suggests that could translate into problems reining in Epstein-Barr virus (EBV) – a common trigger in ME/CFS.  Wyller’s earlier gene expression study, in fact, suggested that B-cell problems could be the key to the EBV problems seen in ME/CFS. Now Wyller suggests that these B-cell problems could result from a complex interaction between TGF-B and cortisol.

Wyller’s going to check out that interaction in a study which will determine how effectively the B-cells in ME/CFS patients respond to EBV in the presence of neuroendocrine hormones. If cortisol or other neuroendocrine hormones impair the ability of B-cells to whack EBV in ME/CFS, Wyller may have uncovered one reason why mononucleosis is such a common trigger for ME/CFS.

Mold Connection?

Wyller’s focus on the research literature apparently precluded him from exploring another TGF-B angle. Mold has become a hot if little studied topic in ME/CFS. For over a decade, mold doctor Ritchie Shoemaker has asserted that elevated TGF-B levels play a major role in mold related illnesses.  Instead of B-cells, though, Shoemaker ties TGF-B issues to T cell problems and reduced blood flow in the capillaries, which translate into reduced oxygen uptake and problems with producing energy in the mitochondria – a key theme in ME/CFS.

Shoemaker, interestingly, asserts those blood flow and immune problems mirror what is happening in sepsis. In fact, Shoemaker believes that the chronic inflammatory response syndrome (CIRS) he sees in his patients is a chronic form of sepsis. Over ten years ago ME/CFS specialist Dr. David Bell proposed a chronic form of sepsis exists in ME/CFS as well.

Could Chronic Fatigue Syndrome (ME/CFS) Be a Chronic Form of Sepsis?

 

Could Chronic Fatigue Syndrome (ME/CFS) Be a Chronic Form of Sepsis?

“In this monograph I would like to explore the concept of neuro-immune fatigue as a metabolic illness resulting from a series of events beginning with an infection, toxic exposure or neurologic injury.” Dr. David Bell, 2007

This is one of a series of blogs highlighting hypotheses mostly written by doctors or other professionals with ME/CFS, or in this case, doctors who have cared for them. The hypothesis examined in this case: Dr. Bell’s idea, produced in his monograph, “Cellular Hypoxia and Neuro-immune Fatigue”, that chronic fatigue syndrome (ME/CFS) could be a kind of “slow sepsis”.

Bell’s “Cellular Hypoxia” book was published in 2007, long before he was probably acquainted with Dr. Naviaux’s and others’ work and before the recent explosion of interest in cellular energy production in ME/CFS. Naviaux and others would probably smile, though, at Bell’s prediction that with ME/CFS and other diseases, “we may be witnessing the emergence of the next era of medicine: the diagnosis and treatment of cellular metabolic diseases”.

Sepsis is a life-threatening response to infection or trauma that can lead to tissue damage, organ failure, and death. In some ways, sepsis sounds similar to autoimmunity. For reasons the medical profession does not understand, sepsis begins when the immune system resets itself, stops fighting pathogens, and turns on the body.

The results are often devastating. The near complete body breakdown that results makes sepsis the most expensive disease hospitals treat.  Forty percent of patients with severe sepsis do not survive.

Chronic Fatigue Syndrome (ME/CFS) – A Mild but Chronic State of Septic Shock?

ME/CFS is obviously not sepsis, but it does share some interesting characteristics.  With his “cellular hypoxia” monograph published in 2007, Dr. David Bell suggested that people with ME/CFS may exist in a “mild, but chronic state of septic shock”. Bell came to this conclusion after finding that sepsis and ME/CFS produces what he believed is a similar kind of oxygen dysfunction. In sepsis and in ME/CFS, Dr. Bell notes that oxygen is actually abundant: it’s abundant in the air, the lungs and the blood of ME/CFS patients, but it’s just not getting taken up by the tissues.

Bell reports that in septic shock, the following events occur (note the last one):

  • a serious infection occurs which –
  • results in the production of cytokines which –
  • increases nitric oxide levels which then –
  • interfere with the production of cellular energy.

Bell noted that when nitric oxide blocks the flow of oxygen in severe septic shock, a patient can still die despite doctors giving him/her as much blood and oxygen as they need.

Bell suggests a similar process to sepsis occurs more gradually in ME/CFS. First, an initiating infection or toxic exposure triggers the immune system to produce pro-inflammatory cytokines and nitric oxide (NO). From there, NO increases peroxynitrite and superoxide (Martin Pall’s hypothesis), which causes oxidative stress and interferes with mitochondrial function.

Ultimately, the cell becomes hypoxic (oxygen-starved), and neuropathies and autoimmune and other problems develop.

The idea that impaired oxygen intake might be limiting energy production has gained some currency since Bell wrote his monograph.  Vermoulen’s exercise studies suggest that impaired oxygen intake, not mitochondrial problems, is the key issue in energy generation. The early stages of Ron Davis’s collaboration with an San Jose State University bio-engineer suggest that the red blood cells may have difficulty getting to the tissues. Other researchers have found autoantibodies to receptors that open and close the blood vessels in a subset of ME/CFS patients.

Last year, Chris Armstrong in, The “Starvation” Disease? Metabolomics Meets Chronic Fatigue Syndrome Down Under“, took the sepsis/ME/CFS notion one step further when he noted that many of the metabolomic anomalies (reduced amino acids, reduced lipids and increased glucose levels) found in ME/CFS are also found in sepsis and starvation.

Remarking that during sepsis, immune cells rely entirely on glycolysis to proliferate, Armstrong speculated, much as Bell did years earlier, that an infection or autoimmune process might have triggered a sepsis-like condition which lead to a state of chronic metabolic starvation.

A last tie to sepsis is an incidental one.  Ron Davis and Ron Tompkins of the Open Medicine Foundation worked on sepsis together. Based on his work there, Davis has said ME/CFS could be a kind of atypical sepsis.

Two Vascular Diseases?

blood vessels

Blood vessel damage could play a central role in both sepsis and ME/CFS

Bell noted that a vasculopathy – inflammation of the blood vessels – was the first symptom (reddened cheeks) he noticed in ME/CFS.  (That suggested to him that a parvovirus may have swept through his area.)

Cardiovascular issues could be central in both diseases. Perhaps the most interesting possible intersection between sepsis and ME/CFS occurs in the blood vessels – specifically the small blood vessels.

Recently an NIH Panel redefined sepsis as: “severe endothelial (blood vessel) dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure”; i.e. at its heart, sepsis is a small blood vessel disease caused by a pathogen attack – which is complicated by the immune storms that follow.

Sepsis has also been called a “malignant intravascular inflammation” characterized by excessive coagulation which blocks blood flows to the small blood vessels, reducing blood volume and lowering blood pressure.

Indeed, as Bell points out several times in his monograph, vascular issues show up again and again in ME/CFS, POTS, orthostatic intolerance and similar, related diseases.

Blood Pressure

Altered blood pressure is another sign of cardiovascular issues in both diseases. A sudden drop in blood pressure associated with an infection is an indication that sepsis has begun.

Blood pressure regulation problems are found in ME/CFS but anecdotal reports suggest that declines in blood pressure may be common as well.  Bell writes that most, but not all, people with ME/CFS have low blood pressure – something that the medical profession has little interest in – unless you’re in the ICU.  It’s ironic, Bell notes, that an ME/CFS patient with a blood pressure 75/40 will get little notice but put someone with that blood pressure in an intensive care unit and the sirens will go off.

Blood Volume

Low blood volume is common in sepsis and great efforts are made to increase it. Low blood volume, of course, is very common in ME/CFS as well. Sometimes blood volume is so low in ME/CFS as to stagger the mind, yet it’s received little attention.

Increasing blood volume can, of course, be helpful in ME/CFS, but is not as helpful as one would think, given the low blood volumes found. (Could microcirculatory problems be to blame?)

Blood Flows

In sepsis, blood flows in the microcirculation become so low as to damage the organs. That doesn’t appear to happen in ME/CFS, but even back in 2007, Bell was able to point out studies showing reduced blood flows to the brain and muscles was present.

Pathogen Damage

Sepsis was long thought to result from an overwhelming immune response to an infection but that’s no longer thought to be true. In 2010, however, that changed. The Working Group on Blood Systems Response to Sepsis, convened by the NIH’s National Heart Lung and Blood Institute (NHLBI), concluded that a cytokine cascade was not, as had been previously believed, the main culprit. The real issue in sepsis, they asserted, is damage to the blood vessels caused by an uncontrolled infection.

The damage is then exacerbated by many inflammatory factors (including Dr. Bell’s nitric oxide metabolites).  A period of reduced immune activation or “immuno-paralysis” (caused by an overactive anti-inflammatory response/immune exhaustion) that follows then sets the stage for the reactivation of latent viruses such as EBV, HSV-1 and others which amplify the damage.

The immune response is still recognized to be important, particularly in the later stages of the disease, but the infections themselves and the damage they do mayt be the key factor.

That’s an intriguing finding given that the biggest factor in determining who gets ME/CFS and who doesn’t after an infection appears to be the severity of the initial infection. Could a severe infection kick off a low-grade, chronic type of sepsis in ME/CFS?

It’s possible that the difficulty NK cells – and probably T-cells – have in killing off pathogens in ME/CFS might just give those pathogens enough time to damage the blood vessels.  Or, perhaps in other cases, an autoimmune process is sparked which does the same. (An autoimmune process appears to occur in some types of POTS).

Post-Sepsis Syndrome (PSS)

Interestingly, sepsis appears to be another potential trigger for chronic fatigue syndrome (ME/CFS). Post-sepsis syndrome (PSS) – a condition occurring in about 50% of sepsis survivors – indicates that surviving sepsis – perhaps like surviving the infection, injury or whatever that appears to trigger the onset of ME/CFS – is often not nearly the end of the story.

Extreme fatigue, problems with cognition, muscle and joint pains, insomnia and other sleep problems, that can last months or even years are common outcomes of sepsis.  In fact, a sepsis trust has produced a support document specifically for post-sepsis patients experiencing “chronic fatigue“.

The medical profession has been content thus far to simply to document the extent of PSS – with little attempt to understand or treat it.  The causes of the fatigue and chronic pain in PSS are completely unknown. This is despite the fact that several studies have made clear that PSS is a significant and enduring problem: statistics suggest that about 250,000 people a year come down with PSS.

The disease is clearly pathophysiological, but the only help The Sepsis Alliance could provide for the many chronically ill survivors was to get emotional and psychological support (counseling, cognitive behavioral therapy or neuropsychiatric assessment) or physical therapies.

Treatment

Sepsis is also confusing to treat. The first line of defense is a hearty dose of antivirals, fluid support, etc.  From there it gets trickier.  People with sepsis may have a pro-inflammatory phase followed by immune suppression (or both may be occurring at the same time).  (Could ME/CFS be a kind of drawn-out sepsis with a longer pro-inflammatory phase followed by immune exhaustion?)

Researchers and doctors focused on reducing pro-inflammatory responses, but drug trials targeting the pro-inflammatory response have been ineffective.  Now, researchers are targeting immune checkpoints in hopes of unleashing the power of the innate immune system.

Check out a more technical take on sepsis and ME/CFS which brings Systemic Inflammatory Response Syndrome (SIRS) into the equation: IS SIRS, CARS, MARS – AND NOW PICS – CAUSING THE “CHAOS” IN ME/CFS?

Conclusion

dr. david bell

Dr. David Bell

Chronic fatigue syndrome (ME/CFS) is not sepsis but the two diseases do share some intriguing characteristics. Both sepsis and ME/CFS often start with an infection; oxygen delivery to the tissues appears to be a problem; blood pressure, blood volume and blood flows are affected, and sepsis often results in a syndrome that symptomatically looks very much like ME/CFS.

As Roberts points out what’s happening in the very, very complex disease known as sepsis is still unclear. Whether or not the new drugs being developed for sepsis will play a role in ME/CFS is, of course, unknown as well. Drugs being developed to turn off the anti-inflammatory response are intriguing given the state of “immune exhaustion” that some studies have found in ME/CFS.  If ME/CFS does turn out to be a kind of “slow sepsis” it will be a good idea to keep an eye on the developments there.

Stevens, in fact, suggests that the ME/CFS and sepsis communities stay in close touch.

It seems logical that the ME/CFS community should begin to share knowledge and resource with the sepsis organizations such as International Sepsis Forum (ISF), Global Sepsis Alliance and Sepsis Trust and Post Sepsis Syndrome patients. The curative challenges ahead are monumental, involving complex pathways which have yet to be researched, and will no doubt result in individualized treatments.

Simmaron Patient Day Part II: The Hanson Report

Maureen Hanson has been making waves.  An ace molecular plant biologist prior to entering the chronic fatigue syndrome (ME/CFS) field, Hanson has worked on mitochondrial and gene studies in plants dating back decades. Now, with her son ill from ME/CFS, she’s turned her talents to this field, and has made a difference in a hurry.

A trusted researcher, Hanson scored one of the few XMRV grants and in a short period of time has produced studies on the gut, mitochondrial DNA, exercise, and metabolomics in ME/CFS. Last year, Hanson, created one the few chronic fatigue syndrome (ME/CFS) research centers in the U.S. (the Cornell Center for Ennervating NeuroImmune Disease, ) and this year she and her colleagues received one of the three NIH ME/CFS Research Center grants. She’s also a member of the Simmaron Research Foundation’s Scientific Advisory Board.

Last year Hanson was awarded a smaller NIH grant (R21) to do preliminary work assessing the energy production in ME/CFS patients’ immune cells using the Seahorse XF Analyzer.  In this blog we take a closer look at the work underway.

A Breakthrough Technology

It’s safe to say that the Seahorse machine is changing how researchers do research. In the mid-2000s the Seahorse folks introduced something new to the medical world called “extracellular flux (XF)” technology. A monolayer of cells is placed in a very small, 10 ml sensor chamber and then stimulated.  Every few seconds a sensor placed 200 microns above the cell monolayer takes a measurement.  Where past techniques required hours to assess oxygen metabolism, the Seahorse can do it in minutes.

This technology allows researchers to determine the energy consumption of cells by analyzing changes in oxygen and acid levels occurring in the media outside of them.  The amount of oxygen present indicates how much energy is being produced through glycolysis and by the mitochondria.

The ability to place energy stimulating or inhibiting or other drugs in the sensor chamber brings the possibilities of the Seahorse machine to an entirely new level. If the inability to produce energy turns out to be a key factor in ME/CFS, the Seahorse machine’s ability to test how drugs and other substances effect the energy production of cells could be a big boon indeed

Agilent, the company that produces the Seahorse machine, reports the machine has been used in over 250 studies. HIV researchers, for instance, recently used the machine to determine the effectiveness of the immune response in HIV patients. It turns out that in order to meet a threat, many of our immune cells undergo a huge metabolic shift as they get transformed from a resting to an active state. That shift coincides with large increases in glycolysis in particular.

A similar approach is being used in chronic fatigue syndrome (ME/CFS). Tomas’ recent Seahorse study suggested that ME/CFS patients’ immune cells (PBMC’s (T, B and NK cells, monocytes))are having severe problems producing energy. Tomas’ study opened up an important possibility but it was limited by its inability to determine which cells were having problems.

https://www.healthrising.org/blog/2017/11/11/cellular-energy-hit-chronic-fatigue-study/

Hanson is taking the next step in assessing immune functioning in ME/CFS with her R21 NIH grant. That grant gave her the funds to assess the energy production of individual immune cells separately (T, B and NK cells).  (Isabel Barao is also examining energy production in NK cells).

Each of these cell types has been potentially implicated in ME/CFS. The T-cell problems Derya Unutmaz of Jackson Labs saw are what attracted him to ME/CFS, and Mark Davis of Stanford recently found signs of unusual clonal expansion in ME/CFS patients’ T-cells.  The success some ME/CFS patients have with Rituximab suggests B-cell issues are present, and the problems ME/CFS patients’ natural killer cells have with killing have been known for decades.

T-cells are a particularly good subject because springing into action to kill other cells or to produce clones of themselves to fight invaders requires enormous amounts of energy. If energy production is flawed in ME/CFS, it’s probably going to show up in patients’ immune cells.

Glycolysis OK

Metabolomic studies suggest glycolysis might be inhibited in ME/CFS, but at the OMF’s Stanford Symposium Hanson stated that she hasn’t found impaired glycolysis. When glucose was given to the immune cells to stimulate their glycolytic processes, the cells were able to use it, but their respiratory capacity (oxidative phosphorylation) was blunted.

In another study, which the SMCI helped to fund, Hanson’s Metabolon metabolomics study found lower glucose levels (a surprise) as well as differences in fat and lipid metabolism (i.e. energy production), and in the sphingolipids that play a big role in Naviaux’s findings.

Hanson noted that low glucose levels are not a good sign, either. Low glucose levels have been associated with increased cortisol responses (possibly leading to exhaustion) and inflammation. Plus they may be able to mess with a person’s endurance.

The last sport anyone with ME/CFS is going to engage in is an endurance race.  That might make sense given that athletes with lower glucose levels tend to do worse in endurance sports. Overall Hanson’s metabolite findings suggest increased inflammation and reduced recovery from metabolic stress are part and parcel of ME/CFS. Metabolic stress, of course, is exactly what she’s measuring in her Seahorse study.

Hanson’s finding of normal glycolysis in ME/CFS patients’ T-cells mirrors the findings of Tomas’ recent Seahorse study. However, Hanson’s early findings are suggesting that, at least in the immune cells, the mitochondria are the issue.

Hanson has found that ME/CFS patients’ T-cells use less of their “respiratory capacity” when provoked than do healthy controls’ cells. If I’m reading this right, the capacity to produce energy is there, but it’s not being used.  The next step is to determine if the T-cells, when they become activated, can produce enough energy to be effective. If Dr. Hanson finds they’re not up to the task of producing adequate energy, she said, “they may also be unable to effectively respond to an immune challenge.”

Lethargic T-cells could have major implications for the immune system, as T-cells are important in just about every immune system activity. At least four different kinds of T-cells exist:  T-helper cells activate B and NK cells, T-killer cells destroy virally infected and cancerous cells, T-memory cells alert the immune system to danger, and T-regulatory cells help keep the immune system humming.  Small studies suggest that cytotoxic or killer T-cells have the same problems with killing infected cells that NK cells do.

Whether or not something in ME/CFS patients’ blood is essentially putting their cells to sleep is one of the more fascinating questions facing this field. Several researchers including Ron Davis of the Open Medicine Foundation and Fluge and Mella in Norway believe something in the blood is doing just that. Energy production issues in ME/CFS patients’ cells that have been isolated from the blood suggest that something may be wrong with the cells themselves. It’s possible, therefore, that problems may lie in both the blood and the cells.

Since the Seahorse machine allows researchers to insert different substances in the medium the cells are bathed in, I asked Dr. Hanson if she could use the machine to determine the effects ME/CFS patients’ blood may be having on their immune cells.

Dr. Hanson replied that the Seahorse machine could determine if something in ME/CFS patients’ serum affects mitochondrial function in immune cells from healthy people, but the Seahorse technology would not be able to tease out what factors in the serum are responsible.

The Seahorse requires large samples of difficult to obtain immune cells. T-cells are relatively easy to obtain; B and NK cells – not so much.  Getting Maureen Hanson the resources she needs to do her work is where the Simmaron Research Foundation comes in: it’s supplying the cells she needs to do her work.  Dr. Hanson stated that, “We are grateful to Simmaron Research for supporting the collection of additional samples from which individual cell types— such as B and NK cells—can be purified for analysis of glycolysis and oxidative phosphorylation”.

Next up, Dr Hanson will analyze the cellular energetics of those NK and B cells. Despite the Rituximab failure, B-cells are still of great interest in chronic fatigue syndrome (ME/CFS). It’s still possible, for instance, that the drug works for a significant subset of patients. Plus B-cells are heavily involved in autoimmunity. Dr. Light has proposed that energy depleted B-cells may increase the risk of an autoimmune process beginning.

The desire to examine NK cells is obvious. Reduced NK cell cytotoxicity is a hallmark of ME/CFS, and reduced cytotoxicity of T-cells appears to be present as well. Could that poor killing power be caused by the most basic of all problems – the inability to generate enough energy? Given the high energy requirements of activated immune cells, that’s a distinct possibility. Dr. Hanson’s work will take us closer than any other yet to answering that most fundamental of all questions.

 

Major Stanford Study Indicates Chronic Fatigue Syndrome (ME/CFS) is Inflammatory Disorder

There’s been a great deal of controversy and confusion surrounding ME/CFS — even whether it is an actual disease. Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.” Mark Davis

There’s nothing like a high-profile study from a major university. For one thing it can get you publication in one of the most prestigious journals around. The  journal the Montoya/Mark Davis study was published in, The Proceedings of the National Academy of the Sciences, is the official publication of the National Academy of Sciences. Its website gets about 21 million hits a month; this study is going to get around.

Dr. Jose Montoya, the leader of the Stanford Myalgic Encephalomyelitis/Chronic Fatigue (ME/CFS) Initiative  has been talking about this study for years. Now that it’s finally here, it’s making an impact with many media outlets picking it up.

The results were positive and that was good news indeed. This was one study we really didn’t want to fail.

Too Big To Fail?

Cytokine signature associated with disease severity in chronic fatigue syndrome patients Jose G. Montoya, Tyson H. Holmes, Jill N. Anderson, Holden T. Maecker, Yael Rosenberg-Hasson, Ian J. Valencia, Lily Chu, Jarred W. Younger, Cristina M. Tato, and Mark M. Davis.  Proc Natl Acad Sci U S A. 2017 Jul 31. pii: 201710519. doi: 10.1073/pnas.1710519114. [Epub ahead of print)

The study examined the levels of a very large number of cytokines (n=51) in the blood of a very large number of patients and healthy controls (ME/CFS=186; healthy controls= 388). Age, sex, race and something called “nonspecific binding” were accounted for.

missing the mark

This was one study we really didn’t want to fail

One of the biggest ME/CFS immune studies ever undertaken, done at a top University, this was a study that we dearly didn’t want to fail. This is the kind of study likely to be labeled “definitive”. It was on scale with the Columbia cytokine study, where co-authors Ian Lipkin and Mady Hornig analyzed 51 cytokines in 298 patients and 348 healthy controls.  If the results of these two hallmark studies were discordant, it would have had negative consequences to any immune interpretation of this disease.

Smaller cytokine studies in ME/CFS have a history of inconsistency, making the similarities in these two studies important.

Results

The first news was not good. The levels of only two cytokines, TGF-Î (elevated) and resistin (lowered) were different in the patients compared with controls.  Displaying an unusual level of consistency for ME/CFS, TGF-B has now been found elevated in about six out of the ten studies it’s been tested in.

TGF-B has not received a lot of attention possibly because researchers are not sure what it means. An anti-inflammatory cytokine that can have pro-inflammatory properties, the authors noted that TGF-B is elevated in a number of dissimilar conditions (cancer, liver disease, inflammatory bowel diseases among others). The authors suggested TGF-B may have pro-inflammatory properties in ME/CFS; instead of tamping down inflammation, they proposed it may be “may be a major factor in promoting relentless inflammation.”

Big Finding

“Remarkably, 17 cytokines were associated with severity in ME/CFS patients.” The study authors

Dr. Montoya got the money for the study and conceived it, and Mark Davis advised him on it, was the senior author of the paper, and tested the samples in his lab.

Davis has won a slew of prizes (The Paul Ehrlich Prize, The Gairdner Foundation Prize, The King Faisal Prize, the General Motors Alfred P. Sloan Prize) and is on the Open Medicine Foundation’s Scientific Board. He’s a big deal in the immune world.

bulls-eye

Montoya and Davis hit the bulls-eye when they threw severity into the mix

I talked to Davis a couple of days after the study’s publication.  I asked him about the main results; those 17 cytokines that predicted severity – was that a lot?  It’s an important question. A couple of cytokines popping out might mean that the immune system is involved but is not a major player – time to look someplace else.  A lot of cytokines showing up, on the other hand, suggests the immune system may very well be it in ME/CFS – time to dig deeper.

Was 17 cytokines a lot? Even in the staid language of scientific journals the surprise at the size of the effect came through: “Remarkably”, the paper said, “17 cytokines were associated with severity in ME/CFS patients.”

When I asked Davis if it was really a lot, I heard him take a deep breath:  “it’s a lot – really a lot” – he said. Getting a third of the immune factors to show up suggests massive immune involvement. Davis – who is involved in constructing immune signatures for different diseases and health – said everything he’s seen about this disease suggests autoimmunity.  That’s a particularly meaningful statement  from such a well-known immunologist. He’s getting to know ME/CFS pretty well: Montoya’s study is the biggest study his public lab has run.

(Mark Davis has two labs – his private research lab and a larger, more public lab he set up to run many more samples at a time. That lab, which got a big federal grant, was designed to bring the same kind of rigor he uses in his private lab to bigger studies.  Researchers like Dr. Montoya can bring their samples to the lab and have the lab test them. That’s what happened in this study)

A Different Kind of Disease?

Mark Davis thinks ME/CFS is probably an autoimmune disease. You don’t see the kind of overt cytokine increases in ME/CFS that are seen in autoimmune diseases like rheumatoid arthritis  and lupus.  This study, in fact, suggested that cytokines were not increased in the patient group as a whole relative to healthy controls.

Adding severity to the mix, however, suggested that cytokines were heavily involved in this disease. Mark Davis said he’d never seen a disease with mostly normal cytokine levels but which presented such clear indications that cytokines affected symptoms.  He suggested that other diseases like Alzheimer’s might display similar patterns if researchers started looking for them.

In an interview with Miriam Tucker, Dr. Montoya echoed the unusual nature of the disease: he simply called the immune activation in ME/CFS – as he has for some time now – a different kind of inflammation.

“Inflammation is much more complicated than two imperfect old measures [sed rate and C-reactive protein]. We’re showing an inflammation that has not been seen before.” Jose Montoya

Three Options?

But what could be causing this bizarre pattern?  Higher cytokine levels could certainly explain the more severe fatigue in some ME/CFS patients, but how do the low or normal cytokine levels explain the fatigue in the more moderately fatigued patients? They do have ME/CFS after all; even if they are less ill than the severely ill, they are still enormously fatigued but their cytokine levels aren’t elevated at all. In fact the cytokine levels are lower than normal in some of them. Three options have been suggested.

(1) Loss of Immune Control In the Severely Ill

One possibility the paper presented is that the healthier patients with lower levels of pro-inflammatory cytokines are able to control them to some extent. Their immune systems are grinding away but they’re keeping – probably at some cost – the pro-inflammatory elements under control. The control mechanisms of the sicker patients, though, have collapsed – they’re bearing the burden of unremitting cytokine activity.

(2) A Localized Infection

In conversation Mark Davis suggested that a localized infection could also be causing the immune system to react – not with the huge increases in cytokines seen in systemic inflammatory or autoimmune diseases but with small, harder to detect ones.  He’s not the first to suggest that. A couple of years ago Michael Van Elzakker proposed exactly that scenario for ME/CFS.

Different

ME/CFS may be a different kind of inflammatory disorder

Van Elzakker proposed that localized infections – probably involving the vagus nerve – were causing small, hard to detect elevations of cytokines. Meanwhile the infections were playing havoc with the vagus nerve’s ability to communicate sensory and immune information to the brain.

I asked Van Elzakker about the study.  He believes the cytokines this study picked up in ME/CFS are probably spillovers from an infection or injury. He cited Robert Dantzer, an important figure in sickness behavior research and pyschoneuroimmunology, who in a (2014) Trends in Neurosciences review, The Neuroimmune Basis of Fatigue agreed that with regard to fatigue:

 “The measurement of circulating concentrations of cytokines represents the main limitation of the present studies on fatigue and inflammation. Given that cytokines are autocrine and paracrine communication factors, their circulating levels have little functional value and represent mostly spillover from the site of cytokine production and action.

Given how profoundly limited many people with ME/CFS are – Van Elzakker believes these localized infections probably exist in the neuroimmune nerves such as the vagus or trigeminal nerves.

(3) Context  – Is Context King?

There’s another possibility. Gordon Broderick’s modeling work in chronic fatigue syndrome (ME/CFS) suggests that context may be king in the immune system.   During a recent phone call Broderick described the co-expression study he did that found a changed immune landscape in ME/CFS.  Cytokines such as IL-1b, 2, 4, IFN-γ, TNF-α  and IL-10 had larger than expected impacts in ME/CFS patients relative to healthy controls while other cytokines had less impact.

If Broderick’s right, none of the cytokines found in Montoya’s study need to be elevated to have a significant effect – they simply have to be embedded in a dysregulated immune network.

Leptin is Back

This is the second time leptin has shown up in a Stanford study, and the researchers suggested that it might be the keeping the chronic inflammatory state in ME/CFS intact. It turns out that adipokines – cytokines secreted by fat cells – like leptin may be able to trigger neuroinflammation. They’re also found in higher levels in women and may be a particularly important trigger in female dominated inflammatory diseases such as multiple sclerosis.

 Duration

In contrast to the Lipkin/Hornig and another study, this study found little evidence of increased cytokine levels earlier in the disease or decreased levels later in the disease. The small numbers of short duration patients (n=30) in the study, however, could have prevented any findings from reaching statistical significance. Interestingly, the study did not find that disease duration was correlated with severity; i.e. patients who had been ill longer were not necessarily worse off.

 Diagnostic Test?

Mark Davis suggested the findings might prove the basis for a diagnostic test but in conversation indicated we’re far from one right now. Much more study is needed.

The diagnostic test problem is greater in the low to moderately ill patients who have similar cytokine levels to healthy controls. How to devise a test to distinguish them from the healthy controls with similar cytokine levels is the big question.

Montoya reported that his team was working on a five-cytokine panel that would require a doctor first classifying each patient by severity. If Montoya can devise specific cytokine signatures for each level of severity, a test might be feasible, but it’s clearly going to be a complex undertaking.

Big Study (Too Big?)

Montoya rather courageously put a lot money into an area of research – cytokine analyses – that have had their problems in ME/CFS. As the Lipkin/Hornig study and this study showed, when it comes to immune studies size is definitely better.

While it is possible that this study had more controls than needed, at least Montoya didn’t err on the other side – too few patients; that might have been fatal to this study. Mark Davis thought that given all the noise in the data, that a smaller study might not have found much.

 Don’t Think Too Much: the Zen of ME/CFS

In a kind of Zen-like statement Mark Davis cautioned about “thinking too much” about this disease at this point.  Davis wasn’t suggesting not inquiring about the disease, but not coming to conclusions about it.  We’re not there yet. We’re more in a space of creative inquiry than anything else.

tea-house-mt-fuji

Mark Davis warned against coming to conclusions; more views of ME/CFS is what we really need

Things got even more zen-like when Davis referred to a famous series of paintings called Thirty-six views of Mt. Fuji to underscore where we are with ME/CFS right now. The celebrated series by Japanese artist Hokusai shows Mt Fuji from different perspectives including from at dawn, from a window in a house, from behind a huge wave, etc., etc.

To Davis, ME/CFS is like Mt Fuji; we need to look at it from a lot more angles to fully understand it. The most important thing we can do now is to test, test, test and let the data guide us.

This study may demonstrate that more than anything. It, after all, had four highly unusual results – very little evidence of immune dysregulation compared to healthy controls; massive evidence (17 cytokines!) on the other hand, that the immune system is effecting severity, a substantial number (on the other, other hand) of individuals with low or low-normal cytokine levels, and finally two cytokines with abnormal levels which didn’t have anything to do with severity at all.

This study, then, boosted interest in the immune system in ME/CFS, while raising a lot of questions about it at the same time. A lot of work – a lot of exploratory work –  remains to be done to figure this puzzle box of a disease out.

In fact, exploration is largely carrying the day in ME/CFS research. Montoya got hundreds of samples, tested them as widely as possible, analyzed them a bit and then stood back. Ditto with the Ian Lipkin/Mady Hornig immune study,  the metabolomics studies from Armstrong and Naviaux, (Naviaux, however, has a hypothesis), Ron Davis and the Open Medicine Foundation with their severe ME/CFS Big Data study, and Avindra Nath and his deep Intramural NIH study.  They’re all exploring.

Mark Davis’ talk at Open Medicine Symposium on Saturday should be a good one.  NINDS Director Dr. Koroshetz talked up Davis’s exciting findings in the recent NIH Telebriefing, and Ron Davis thinks they may be even more significant than this paper. If you’re at the Symposium you can ask him about his work or Mt Fuji or just say hello and thanks.

Treatment

This study is a major legitimizer and a big spur for more immune studies – particularly big immune studies. One thing it doesn’t present are clear treatment options. When I asked Mark Davis about treatment options, he was unwilling to commit to any line of treatment based on the results. He agreed that basing treatment options off of this study would be like shooting fish in a barrel.

That doesn’t mean the study won’t help on the treatment end. The severity results, after all, scream inflammation. That suggests anti-inflammatories might very well help. Ron Davis noted that many immune affecting drugs are under development right now which might be useful for ME/CFS in the future. We simply need more study to assess which targets might be best.

If Gordon Broderick’s right, though, it may take more than knowing a cytokine’s levels to find the right target. Broderick’s working on complicated models that incorporate the effects hormone levels, in particular sex hormone levels, have on immune factors in ME/CFS.  Broderick believes he’ll be able to devise a treatment approach that pushes the immune system one way and then another in order to nudge it back to a stable and healthy state.

Fatigue or Functioning?

While the multi-dimensional fatigue index used to assess fatigue has been validated as a good measure of fatigue across many diseases, one wonders if a functionality scale might have worked better. Fatigue is what ME/CFS is known for, but it’s real impact is on functioning. It’s possible to be very fatigued and still work, or to be pacing effectively – and not doing much work – and be less fatigued.

The MFI worked well in this study and past ME/CFS studies have used it, but one wonders if a scale that tracks functionality – how much activity one is actually doing – might have been more effective at tracking severity.

 Slow Progress

Montoya has been given much (reportedly $8 million donation in 2008) and promised much, but the ME/CFS work has been slow. He’s a toxoplasmosis expert, possibly the top expert in the country, and he’s been pouring out toxoplasma studies – fourteen since 2015 – but the work in ME/CFS has gone much slower.  Since 2009 he’s been the senior or lead author on just four ME/CFS studies – two of which involved the valganciclovir trial and predated the opening of his ME/CFS center.

This latest study was the most important one – it will undoubtedly help the field – but one hopes that with this monster study out of the way Montoya will be able to move faster on his other ones. His current research projects page lists ten studies. Two involve the Zinns who, unable to publish their work at Stanford, exited to work with Lenny Jason. Those studies are surely not extant.

The eight others, though, involve brain imaging, neuroendocrine, gene expression, cardiovascular, immune and pathogen studies. In a telephone conversation Mark Davis referred to some scintillating results he and Montoya are working on using the immune data Montoya gathered.  Let’s hope we’ll see those results and more from Montoya’s Chronic Fatigue Initiative in the not too distant future.

Conclusion

lighthouse

This study, as did the Lipkin/Hornig study, suggested you have to approach ME/CFS differently than other diseases to be successful.

One of the things that emerged from this study is that ME/CFS really, really is different and woe to any researcher who assumes that it’s not. The regular rules of the road do not apply – you can’t just measure cytokine levels and expect to get anything. You have to dig deeper, and what this study and the large Lipkin/Hornig study before it demonstrated was that if you do dig deeper, you might stumble on something extraordinary.

The study’s excellent pedigree – it’s size, the lab it took place in and the journal it was published in – guarantees it will get noticed and that’s a good thing. The most important aspect of the study may be the legitimization it confers on the illness. Hopefully the study will introduce new researchers intrigued by what could be a new type of inflammatory disorder to the field.  While more work is needed, the study also points to possible future effective treatment options. Lastly, the study indicates, as did the Lipkin/Hornig study, that bigger really is much, much better in ME/CFS research. Hopefully funders will take a cue from these large studies, and support the bigger and more definitive studies this disease needs to move forward.

 

 

 

 

 

 

 

 

 

 

 

 

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

subsets chronic fatigue

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.

SR_Donate_6.9.14_5

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

foundational study

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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The Shift: Top Science Journal Asserts Shift in Attitude Towards ME/CFS Has Occurred

“Chronic Fatigue Syndrome is a biological disease” Dr. Ian Lipkin’s Center for Infection and Immunity at Columbia University

From NIH Director Francis Collins’ high profile blog “Moving Toward Answers in ME/CFS“, to the New York Times Opinion piece “Getting It Wrong on Chronic Fatigue Syndrome” exposing the failures of the PACE trial, to the coverage of the Australians’ search for a biomarker, the chronic fatigue syndrome (ME/CFS) community has been treated to some excellent press lately.

difference-maker

Influential journal suggests a shift is occurring in how researchers are viewing ME/CFS

Now comes a piece “Biological underpinnings of chronic fatigue syndrome begin to emerge” from the news section of Nature, one of the world’s most read and most prestigious scientific journals. The article, written by Amy Maxmen, proclaims that a “shift” from viewing ME/CFS as psychosomatic to viewing it as a real disorder has occurred.

The article is a far cry from some of sentiments of the “Life After XMRV” piece Nature did in 2011 in which Simon Wessely asserted that the patients’ reactions to that finding would lead another generation of researchers to avoid ME/CFS research.  (He rather memorably suggested that researchers would rather “work on images of Mohammed” than study it.) Even advocates for the disease, though, worried that the controversy would turn off researchers.  Others, however, felt that the XMRV finding would galvanize researchers to use new technologies to understand ME/CFS.

They were right. Wessely, it appears, was wrong.

World-Class Researchers Beginning to Take ME/CFS On

The Nature article makes it clear that a major cause for the shift occurring is the presence, for the first time ever, of world-class researchers willing to take ME/CFS on.

Dr. Ian Lipkin, an immunologist with an unmatched resume, has not only lent his name and prestige to this disease, but his Columbia team’s published findings  – two of which have outlined dramatic changes in immune functioning in ME/CFS –  have been at the center of this shift. The Columbia team’s findings have been built on collaborations with expert clinicians, including Dr. Daniel Peterson and the Simmaron Research Foundation he advises. (Check out the slideshow that dominates the website for Lipkin’s Center for Infection and Immunity (CII): one of the slides simply says, “Chronic Fatigue Syndrome is a biological disease”.)

Ron Davis, with his many awards and the stunning story of his son’s illness, is also reaching deep into the scientific world to find answers. The stunning picture of Davis holding the printed circuit he’s using to decipher ME/CFS could be a metaphor for the search for the answer to ME/CFS itself.  The answer is there in that maze somewhere, and it’s going to be technology – probably new technology – that uncovers it.

These two men, with their willingness to publicly take bold stands for this disease, have been at the forefront of the “shift” that appears to be occurring. Both men have had the ear of the NIH Director, Francis Collin.  Their credibility has gone far in helping the National Institutes of Health, the largest funder of biomedical research in the country, take a reinvigorated approach to ME/CFS.

Dr. Avi Nath

Dr. Avi Nath, National Clinical Center, NIH

Next, Nature cites the conclusion from the IOM report’s “expert panel” that  chronic fatigue syndrome is an under-studied physiological illness. Then comes mention of the intramural study led by Avindra Nath, the widely published and respected clinical director for the National Institute of Neurological Disorders (NINDS). An infectious neurologist, Dr. Nath is conducting the first intramural study in ME/CFS in decades at the National Institutes of Health Clinical Center. Dr. Lipkin and Dr. Peterson are advisers on this intramural study.

Others could have been mentioned: Mark Davis of Stanford, Derya Unutmaz of the Jackson Laboratory, Lasker Award winner Michael Houghton of the University of Alberta, Patrick McGowan of the University of Toronto and others new to the field.  As the names line up, you do get the idea that, as Dr. Nath told Nature, “Researchers are thinking deeply about how to build the field.”

Building the field, of course, is what the NIH’s recent decision to fund three ME/CFS research centers is all about. Yes, much more is needed, but this article, showing up in a highly cited journal, suggests that the tide may be slowing turning where it needs to turn the most – in the research community.

Ian Lipkin and the Center for Infection and Immunity Step Forward

 Ian Lipkin is featured twice in the article, first stating:

“We now have a great deal of evidence to support that this is not only real, but a complex set of disorders. We are gathering clues that will lead to controlled clinical trials.”

Lipkin has been a vocal advocate for ME/CFS

Lipkin has been a vocal advocate for ME/CFS

Three studies from Lipkin and Hornig at Columbia are expected to be published shortly with one to be published next week. Don’t be surprised if, based on Lipkin’s comments, the CII lays the groundwork for something the chronic fatigue syndrome (ME/CFS) community has been waiting for a long time: evidence of biologically determined subsets, or in Lipkin’s words, direct evidence that ME/CFS is made up of a “complex set of disorders”.

The Simmaron Research Institute / Center For Infection and Immunity Collaboration

Simmaron CII partnership

Simmaron and the Center for Infection and Immunity: working together to understand ME/CFS

In its efforts to scientifically redefine ME/CFS, the Simmaron Research Foundation regularly partners with Dr. Lipkin’s Center for Infection and Immunity. Recent efforts included the spinal fluid study which showed dramatic alterations in immune functioning in the brain, the immune study which differentiated short from long duration ME/CFS patients, and the gut study about to be published. Simmaron is currently collaborating with the CII on additional phases of spinal fluid research and more.

Stay tuned for a Simmaron/CII study that will help to reshape our understanding of what ME/CFS is and how it should be treated.

Simmaron

The Gut and ME/CFS

The gut with its immense effect on the immune system is proving to be a fertile area of research on ME/CFS (see below). Perhaps no other team has pushed the ME/CFS gut connection more effectively recently than Ian Lipkin and Mady Hornig at the CII.

The Nature piece tantalized us a bit with news from Ian Lipkin that one of those studies showing an unusual pattern of gut flora in people with ME/CFS and IBS will be published soon.

A quick look at what studies have told us (see below) about the gut and chronic fatigue syndrome (ME/CFS) suggests that reduced gut floral diversity, possibly characterized by increased numbers of inflammatory bacteria may be common in ME/CFS.

Importantly, every study that has looked for leaky gut – which involves the translocation of gut bacteria into the blood – where it could spark an immune response causing fatigue, pain and other symptoms – has found it.  Most intriguingly, the research suggesting that exercise may negatively affect ME/CFS patients’ gut flora and increase their leaky gut issues could help explain post-exertional malaise.

The Gut and ME/CFS – Recent Findings

  •  Exercise in ME/CFS produces changes in gut flora, leaky gut and Inflammation  – Shukla’s 2015 study suggests that exercise not only changes the composition of the gut flora in people with ME/CFS but results in increased levels of gut bacteria leaking into the blood (possibly causing inflammation and post-exertional malaise.) The fun didn’t stop there. The ME/CFS patients also had more trouble clearing the gut bacteria from their blood than the healthy controls.
  • People with ME/CFS have reduced gut flora diversity and leaky gut – Gilotreaux’s 2016 study suggests more pro-inflammatory and fewer anti-inflammatory gut species are present in ME/CFS, and provides more evidence of bacteria sneaking through the gut lining and ending up in the blood.
  • Gut bacteria/viruses are infectious triggers in ME/CFSNavaneetharaja’s 2016 review paper suggests that gut bacteria and/or viruses have been overlooked in the search for an infectious trigger in ME/CFS.
  • ME/CFS is associated with reduced gut microbiome diversity and increased gut viral activity – Gilotreaux’s 2016 case report of twins found reduced VO2 max, decreased gut bacterial diversity and increased gut viral activity in the sick ME/CFS twin.
  • Antibiotics can improve gut flora and sleep in some ME/CFS patientsJackson’s 2015 Australian study suggests that erythromycin improved the gut flora and sleep in about a third of ME/CFS patients but not in the rest.
  • Altered gut flora diversityFremont’s 2013 study shows increased abundance of the same bacterial family (Firmicuties) in ME/CFS as found in Shukla’s 2015 study.
  • Leaky gut is associated with an autoimmune processMaes 2013 study suggests that increased bacterial translocation (leaky gut) is associated with high levels of antibodies targeting serotonin. Patients with these antibodies had evidence of increased inflammation.
  • Leaky gut is associated with inflammation and symptom severityMaes 2012 study suggests ME/CFS patients are mounting a very strong immune response to intestinal bacteria found in the blood that is leading to increased inflammation.
  • IBS/leaky gut subset is present in ME/CFSMaes 2012 study shows one subset of ME/CFS patients (60%) has leaky gut and IBS while another subset does not.
  • Treating leaky gut in ME/CFS can reduce symptomsMaes 2008 study shows that treating leaky gut with natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc in conjunction with a leaky gut diet can significantly improve symptoms in ME/CFS

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Inflammation Test Could be Tailor-Made for Chronic Fatigue Syndrome: Are the Mitochondria To Blame?

February 12, 2017

“More than 90 percent of all noncommunicable diseases of aging are associated with chronic inflammation”  David Furman  – Stanford Institute for Immunity, Transplantation and Infection

Inflammation is a big deal in the medical world.  Even mild inflammation, if it’s consistently present, is known to increase one’s risk of getting cardiovascular diseases, diabetes, Alzheimer’s and many others. Standard tests for inflammation such as C-reactive protein or cholesterol, however, are often unrevealing. For instance, inflammation is a key driver of heart disease, but the first sign for many of heart problems is still a heart attack.

inflammation

Chronic, low levels of inflammation are found in many serious diseases.

Likewise it’s been said that chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are inflammatory diseases, but standard tests for inflammation often indicate that none is present. Dr. Montoya believes that current inflammation tests are missing a lot and that future tests will be able to detect the kind of inflammation occurring in ME/CFS.

Given that tests for inflammation are relatively crude, it makes sense that significant efforts would be directed to developing a better test.  It’s no surprise that Mark Davis at Stanford is involved.

Davis’s Institute for Immunity, Transplantation and Infection is spitting out interesting findings like there’s no tomorrow.  Coffee drinkers and dark chocolate lovers were recently pleased to learn that metabolites associated with caffeine and dark chocolate were associated with increased longevity and reduced inflammation. In fact, incubating cells with these metabolites  shut off their inflammatory response.

A 2015 study overturned decades of perceived wisdom that self-attacking or auto-reactive lymphocytes are mostly weeded out early in childhood. (They’re actually very common in adults.)  Davis upended another pillar of orthodoxy when he determined that environment – the microbes, toxins, foods, etc. that we encounter – have far more of an impact on our immune system than our genes. Davis found, for instance, that a single cytomegalovirus infection causes stunningly large and permanent changes to our immune systems.

Davis is bold enough to want to replace all mouse research forever (“Free the mice!”) with a human based approach using immune modeling. In 2015 the Bill Gates foundation gave him $50 million to figure out how to build more effective vaccines. Lastly and most importantly for us, Davis is one of the luminaries sitting on the Open Medicine Foundation’s Scientific Board.  A friend of Ron Davis, I met him at the Davis’ Palo Alto fundraiser a year or so ago. (He said when Ron Davis asks you to do something, you do it).

Davis may have come up with the best test yet for inflammation – an apt subject for ME/CFS and FM patients.  In fact this test sounds like it was made for people with chronic fatigue syndrome and fibromyalgia.

 Old Before Their Time?

The study originated in an attempt to quantify the link between inflammation and something perhaps pertinent to chronic fatigue syndrome and fibromyalgia – aging.  While the evidence is sketchy, it does suggest that people with ME/CFS and/or FM might be aging faster.  Decreased brain gray matter, shortened telomere lengths,  gait alterations, and the cognitive and sleep issues, could all reflect a group of patients who are aging a bit before their time.

The Study

Scientists develop inflammation test that may predict cardiovascular disease Cell Syst. 2016 Oct 26;3(4):374-384.e4. doi: 10.1016/j.cels.2016.09.009. Epub 2016 Oct 13. Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans. Shen-Orr SS1, Furman D2, Kidd BA2, Hadad F3, Lovelace P4, Huang YW4, et. al. 

In this study researchers studied two groups of 40 individuals, one between 40 and 60 years old and one over the age of 60, for nine years. Every year they threw a battery of specialized immune tests at them, and at the end of the study assessed their cardiovascular health by measuring levels of atherosclerotic plaque, arterial stiffness and ventricular function.

Their goal  – to develop a better immune test that can predict cardiovascular risk due to inflammation much earlier than is currently possible.

“Wired and Tired” Immune Systems Spark Inflammation

They hit the jackpot when they measured immune cells responsiveness to cytokines.  Younger study participants demonstrated a quick and dramatic response to the cytokines- their T-cells went into a tizzy, but the older participants produced a more muted response.

Exhausted immune systems

Tired immune systems may be sparking inflammation

We usually think of immune activation as potentially bad – as a driver of inflammation, and  so it is at times. This study suggests, though, that the kind of immune activation present is the key.

The older persons’ immune systems were, in fact, overly activated – but not in response to the cytokines. They were hyped up before the cytokine test; i.e. they were mildly activated (“wired and tired”?) all the time.  When presented with a stressor, though, the immune cells pooped out.

If that pattern sounds familiar, it should.  ME/CFS/FM patients appear to have activated sympathetic nervous systems at rest which also poop out when they’re put under strain. ME/CFS/FM patients low heart rate variability (HRV) scores also demonstrate a less responsive system is present.

A cytokine responsiveness score (composed of 15 different cytokine responsiveness tests) indicated that the always-on-but-muted immune response to danger was not good news. It was associated with signs of atherosclerosis and the inability of the heart to relax between beats.

This study suggests that it’s not the big burst of immune activity that is perilous for most of us. A nice, sharp increase in immune responsiveness is actually a sign of health. It’s the always on, lower levels of immune activation that cause the inflammation that results in so much trouble for so many people – and perhaps in ME/CFS.

It suggests the system doesn’t have to be fully activated to create inflammation; it simply has to be exhausted. The reduced blood and spinal fluid cytokine levels Lipkin and Hornig found in ME/CFS smacked of immune exhaustion. The Columbia-Simmaron Research spinal fluid studies that published those results continue in an effort to characterize the neurological levels of inflammation and immune response and move us closer to treatments.

Several studies suggest that increased oxidative stress and vascular characteristics of people with chronic fatigue syndrome may put them at increased risk of cardiovascular issues.  Improperly functioning mitochondria can produce massive amounts of free radicals and thus inflammation, which in turn furthers hampers mitochondrial functioning.

A Mitochondrial Immune Connection?

Any discussion of “exhaustion” has to touch on the mitochondria.  It turns out that immune exhaustion may very well be linked to mitochondrial problems.

Early on Ron Davis suggested that energy problems in ME/CFS could be affecting the immune cells in particular. Immune cells typically don’t use a lot of energy until they come upon a pathogen, at which point they use enormous amounts of energy to transform themselves into fighting machines that attack the defender and pump out scads of cytokines.  If mitochondrial dysfunction is present it might very well show up in the immune cells in spades.

Armstrong and McGregor’s metabolomic findings suggested that ME/CFS patients were in energy depleted states similar to those found in inflammatory, sepsis-like conditions or starvation.  Their work suggested that energy depletion (immune exhaustion?) may be associated with inflammation in ME/CFS.

Naviaux believes the mitochondria provide our first and perhaps most precise reflection of immune health.  His insights into the mitochondria/immune interface has guided much of his work.

SMCI Tackles Mitochondrial-Immune Connection

The Solve ME/CFS Initiative is exploring the intersection between the immune system and the mitochondria in a slate of studies. In the “The Bioenergetic Health Index of NK Cells as a Diagnostic Tool for Chronic Fatigue Syndrome” Isabel Barao – an ME/CFS researcher who’s also worked with the Simmaron Research Foundation – will assess the energy index of NK cells in ME/CFS.  This new test, called the “Bioenergetic Health Index,was developed at the same University Jarred Younger is working at (University of Alabama at Birmingham).

low energy chronic fatigue

ME/CFS researchers are determining if low energy production is affecting immune performance

Another SMCI study “Metabolic Analysis of B-Cell Maturation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” will assess whether mitochondrial problems are affecting the B-cell problems that Rituximab may be fixing in ME/CFS.  Fluge and Mella – the originators of the Rituximab treatment regimen in ME/CFS – believe autoimmune processes may be attacking the mitochondria in ME/CFS.

A third study “HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS” will determine if HHV-6 infection is affecting mitochondrial energy production in ME/CFS.

The Stanford immune responsiveness test is not available yet. Too expensive for clinical use, researchers are trying to find ways to lower its cost. When the Stanford test becomes available it might not be surprising to find ME/CFS and FM patients scoring very low.

In the meantime ME/CFS researchers are avidly exploring the intersection between the immune system and the mitochondria.

Simmaron