All posts in Immune System

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

March 21, 2016

When we think of immune problems we often think of the immune system going berserk and attacking healthy cells but another kind of immune issue called can be present. Recent studies suggest immune exhaustion may be more of a problem for many chronic fatigue syndrome (ME/CFS) and/or fibromyalgia patients than an immune system run amok.

CHRONIC FATIGUE SYNDROME (ME/CFS)

“I think what we’re seeing is an immune system exhaustion over time” Dr. Mady Hornig

Chronic fatigue syndrome (ME/CFS) has generally been thought of as an immune activation disorder. Although much of the interest in the Lipkin/Hornig 2015 study focused on the immune activation found early in the disease, the study found 13 downregulated immune factors in the plasma of longer duration patients relative to the healthy controls.  Remarkably the same cytokines that were upregulated early in the disease were downregulated later in the disease.

exhaustion

Are ME/CFS and fibromyalgia immune exhaustion disorders?

That pattern smacked of something called “immune exhaustion”. Immune exhaustion is a well-known pattern of immune depletion seen in people with chronic infections or autoinflammatory diseases.  Immune exhaustion may be the main reason why some people just can’t knock an infection.

The patterns seen in the big 2015 Lipkin/Hornig Chronic Fatigue Initiative immune blood study were intriguing but not conclusive. Studies published since then, though, suggest that immune exhaustion – not immune activation – could be the main culprit in people with longer duration chronic fatigue syndrome (ME/CFS) and fibromyalgia.

It should be noted, again, how important it was to differentiate shorter from longer duration patients. No immune abnormalities when the two subsets were mixed; only when they were differentiated by disease duration did the immune issues pop up.

The Simmaron Research/Lipkin/Hornig Spinal Fluid Study

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI.Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31.PMID: 25824300

Next came the Lipkin/Hornig/Simmaron Research Foundation study examining immune factors in the spinal fluid of ME/CFS and multiple sclerosis patients and healthy controls. Not only was a broad pattern of immune inhibition found in the longer duration patients but for the first time match between blood and spinal fluid study was found: the same issues appeared to be occurring in both the central nervous system and the body.

The number of downregulated immune factors – twenty-one in all (vs 13 in the blood study) in the spinal fluid of longer duration ME/CFS patients relative to healthy controls was notable and suggested that the closer one moves to the brain the more evidence of immune exhaustion one may find.

Both ME/CFS and MS patients exhibited immune exhaustion compared to healthy controls but the degree of immune exhaustion seen in ME/CFS was greater than that seen in MS. Demonstrating how complex the immune system is, the two diseases differed more from each other than from the healthy controls.

viral infection

An upregulated chemokine suggests that a viral infection could have triggered central nervous system changes in ME/CFS and MS

In one perhaps important way, though, they were quite alike. A chemokine called CXCL10 that clears the way for the entry of natural killer cells and T lymphocytes into the brain in response to a viral infection was increased in both disorders.  Increased levels of that chemokine in conjunction with the different kinds of immune exhaustion found in both disorders suggests that either different viruses could be present or a different response to the same virus has occurred.

The fact that infectious mononucleosis or glandular fever increases the risk of coming down with either ME/CFS or multiple sclerosis is intriguing in this regard. Could ME/CFS and MS simply reflect differing responses to the same virus?

Jarred Younger recently suggested that MS may be a more damaging form of ME/CFS. Neuroinflammation is present in both, but in one (MS) the neurons are damaged and in the other (ME/CFS) they are not.

Very high levels of CXCL10, such as appear to be present in MS, are associated with nerve damage. More moderately raised levels, such as seen in ME/CFS, are not. CXCL10 levels may also be able to tell us which patients respond better to antivirals. Hepatitis C and HIV patients with higher CXCL10 levels responded less well to antivirals than patients with lower levels.

The Lipkin spinal fluid study is looking more and more like it could end up being a seminal study.  It highlighted a new subset – “the Peterson subset” and validated and expanded on the dramatic immune downregulation seen in the earlier blood study.

A follow-up Simmaron Research/Lipkin/Hornig spinal fluid study is in the works.

The spinal fluid study wasn’t the end of the trend towards immune downregulation, though; right on its heels came the large Landi-Houghton blood study.

The Simmaron Research Foundation Australian Spinal Fluid Study

Mediators Inflamm. 2015;2015:929720. doi: 10.1155/2015/929720. Epub 2015 Mar 5.Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis.

The Simmaron Research Foundation also participated with Sonya Marshall-Gradisnik at Griffith University in a small pre-pilot spinal fluid study. In this smaller study only one immune factor, IL-10, significantly differed between the ME/CFS patients and the healthy controls but the trend was the same; IL-10 was significantly reduced in the ME/CFS patients.

This study may tell us how immune depletion in one area can lead to immune activation in another. Because IL-10 is an anti-inflammatory, reduced IL-10 levels in the cerebral spinal fluid could reflect a brain with inflammation.

The Houghton-Landi Blood Study

Cytokine. 2016 Feb;78:27-36. doi: 10.1016/j.cyto.2015.11.018. Epub 2015 Nov 28. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Landi A1, Broadhurst D2, Vernon SD3, Tyrrell DL4, Houghton M5.

Michael Houghton isn’t just any researcher. A Lasker award winner, he got bit by the ME/CFS bug during the XMRV saga. (He got bit so hard that the Solve ME/CFS Initiative even got him onto the federal advisory panel for ME/CFS ( CFSAC) for a while.)  Researchers of his ilk are a real asset to our community and it’s good to see him remaining engaged. In this study he worked with Bateman-Horne Center’s “Research Czarista” Suzanne Vernon.

The Landi-Houghton study examined 34 immune and growth factors in no less than 100 longer duration ME/CFS patients.  This study also found little evidence of overt immune activation. Instead,  a cluster of down-regulated immune factors ( IL-16, IL-7 and VEGF-A) popped up which suggested ME/CFS –  at least in its later stages – was more characterized by immune depletion. They also suggested that ME/CFS patients might be a aging a bit more rapidly than normal.

Early Aging?

 

Immune depletion showed up in longer duration patients in the Houghton study

Immune depletion showed up in longer duration patients in the Houghton study

IL-7 plays a critical role in NK and T-cell proliferation and induction and IL-7 levels are associated with cognitive declines during aging. The authors suggested that the immune signature they found could mimic aging. It’s not the first result to suggest early aging may be present in either ME/CFS or FM.

One FM study found cognitive declines suggestive of people who were twenty years older.  Reduced telomere lengths (a sign of aging) were found in the white blood cells for FM patients and the CDC has reported finding reduced telomere length in chronic fatigue syndrome as well.

Two Factors Stand Out

VEGF-A – VEGF-A promotes the survival and stability of endothelial cells lining the blood vessels, stimulates muscle and blood vessels and has neuroprotective factors.  It also promotes neuron growth by stimulating epithelial cells to release BDNF – which appears to be low in ME/CFS.

VEGF-A is becoming a factor to look out for in ME/CFS. For one thing it affects the blood vessels. For another reduced VEGF-A levels also popped up in the Simmaron Foundation/Lipkin/Hornig spinal fluid study and in a Gulf War Syndrome study .

Eotaxin – Eotaxin has suddenly appeared on the ME/CFS scene. It was one of only two factors upregulated in the spinal fluid study. Remarkably, high eotaxin levels have been found in long duration patients in three recent studies.

Increased levels of eotaxin have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age.

These consistently increased eotaxin levels could signify either an allergic response a central nervous system infection.

FIBROMYALGIA

The results of immune studies in FM are mixed but three recent studies suggest a scenario of immune depletion may be occurring in FM as well.

A 2012 study found that immune cells from FM patients that were stimulated with an antigen failed to respond as readily as did those of healthy controls.  The dramatic reductions – from 1.5 fold to 10-fold of normal – were found across a wide range of immune factors (IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β, MCP-1 and MIP1-α).

Another fibromyalgia study found a “stark decrease: in the levels of three Th2 cytokines (IL-4, IL-5, and IL-13). Because the cytokines with lowered levels had anti-inflammatory effects the authors speculated that inflammation might be increased in FM. Note that reductions of these anti-inflammatory cytokines (and IL-10 in ME/CFS) might be all that is needed for normal levels of pro-inflammatory cytokines to produce inflammatory effects.

Similar trends toward reduced levels of anti-inflammatory cytokines has also been found in  depression.

Exercise Study Reveals Immune Depletion

J Neuroimmunol. 2014 Dec 15;277(1-2):160-7. doi: 10.1016/j.jneuroim.2014.10.003. Epub 2014 Oct 18.Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia. Torgrimson-Ojerio B1, Ross RL2, Dieckmann NF3, Avery S4, Bennett RM5, Jones KD6, Guarino AJ7, Wood LJ8.

Another fibromyalgia study found a marked difference between the immune and hormonal responses of healthy controls during exercise and FM patients. Four anti-inflammatory factors (IL-6, IL-10, ACTH, and cortisol) increased and two pro-inflammatory factors (TNF-a, IL-8) decreased during exercise in the healthy controls.

The anti-inflammatory response, however, was blunted in FM patients (ACTH, cortisol, and IL-10)  during exercise.

exercise fibromyalgia

Exercise was associated with immune depletion in one fibromyalgia study.

This study also found normal IL- 6 levels which was a surprise given the reductions in IL-10 (another anti-inflammatory cytokine) found.  (IL-6 production by the muscle cells during exercise is believed to trigger IL-10 production.)

That odd finding suggested another way to inhibit anti-inflammatory activity. The authors speculated that FM patients’ muscles may be pumping out normal levels of IL-6, but the signal IL-6 produces to create anti-inflammatory products is simply not getting through.

They suggested that a reduced anti-inflammatory response during exercise could very well play a role in the pain FM patients associate with exercise. Anti-inflammatory cytokines stop the pain receptors on nerves from being activated. Take away those cytokines and FM patients could experience increased pain during exercise.

The authors proposed that a quick immune hit during exercise could be responsible for lasting pain, stiffness and fatigue FM patients experience after exercise.

Conclusion

While some studies differ, recent studies suggest a broad pattern of immune exhaustion may be taking place in both chronic fatigue syndrome and fibromyalgia. That exhaustion is most likely caused by what Lipkin and Hornig called an “exuberant stimulation” of the immune system due to an auto-inflammatory process or a chronic infection.

It’s possible that exhaustion in one part of our carefully balanced immune systems could lead to undue prominence of another part.  Lipkin and Hornig suggested the immune reductions in the spinal fluid found suggested that immune activation might be occurring in the central nervous system. Likewise the FM study suggested the depletion of Th2 factors suggested immune activation could be occurring even though levels of pro-inflammatory cytokines were not increased.

Immune exhaustion is a serious issue in several diseases and efforts are being made to battle it. How the medical profession is tackling immune exhaustion is a subject for another blog.

Ian Lipkin: Three to Five Years* to Solve Chronic Fatigue Syndrome (ME/CFS)

December 26, 2015

Ian Lipkin flew to Lake Tahoe this December to fundraise for work he’s doing with the Simmaron Research Foundation. In a talk covering his virus hunting career, the threat of pathogens to humanity, and his work with chronic fatigue syndrome (ME/CFS), he dropped a bombshell: he stated that he believes it’s possible to solve ME/CFS in three to five years. 

On that hopeful note, let’s learn more about Dr. Lipkin, his work, and his collaborations with Simmaron.

Dr. Peterson’s Introduction

Lipkin’s Columbia Center for Infection and Immunity (CII) has established close ties with the Simmaron Research Foundation. Only a couple of months before, his chief collaborator, Mady Hornig (and Simmaron Scientific Advisory Board member) had given a talk.  Now Ian Lipkin was here.

Dr. Peterson started his introduction of Ian Lipkin by noting that he’d known him since they crossed paths in the 1980’s when Dr. Peterson sent him patients suffering from HIV/AIDS.

Lipkin has changed the ways researchers identify pathogens

Lipkin has changed the ways researchers identify pathogens

Ian Lipkin began a new era in pathogen detection when he became the first researcher to isolate a virus (Borna disease virus) using genetics.  He identified the West Nile Virus that had throw New York City into a panic, developed technologies to identify SARS and then hand carried 10,000 test kits to Beijing at the height of the outbreak. He most recently discovered a highly dangerous virus that recently jumped into humans called MERS (Middle Eastern Respiratory Syndrome Coronavirus).

Lipkin has pioneered many technological breakthroughs in finding pathogens including the use of MassTag-PCR, the GreeneChip Diagnostic, and High Throughput Sequencing. His latest breakthrough is the development of a new screening technique that enhances researchers ability to find viruses 10,000 fold.

Called the top virus hunter in the world, Ian Lipkin runs the Center for Infection and Immunity at Columbia, and is the director of the Center for Research in Diagnostics and Discovery (CRDD) at the NIH. He also worked closely with Steven Soderbergh on his film Contagion.

Ian Lipkin Talks

Who says brilliant scientists can’t be a hoot to listen to as well? Ian Lipkin’s presentation was both enlightening and at times hilarious. Exhibiting a wry sense of humor, Lipkin poked fun at himself and virtually everyone around him.

The last time he was in Lake Tahoe, he said, was in 1984 and he hearkened back to the HIV/AIDS patients Dr. Peterson sent him in the early 1980’s.

“When you come to a fork in the road – take it!”

He stated the guiding principle in the search for pathogens could be summed up by the great Yogi Berra’s adage “When you come to a fork in the road – take it!”.

HIV/AIDS was the beginning of many changes. Even after the medical community knew it was being passed in the blood it still took them 2 1/2 years to find it. (In a Discover interview,  Lipkin noted that he ran the first clinic in San Francisco that would treat HIV/AIDS (then called GRID) patients with neurological problems. Note an iconoclastic element to Lipkin that showed up early in his career: he was willing to see patients others wouldn’t. Check out Lipkin’s fascinating story of how HIV/AIDS lead to him to study infectious diseases.)

Lipkin-chronic-fatigue-syndrome

Lipkin first showed a willingness to support underserved groups early in the HIV/AIDS epidemic

Lipkin then worked on a virus which demonstrated the effects a persistent viral infection can have on the central nervous system.

Next, in another story with possible overtones for chronic fatigue syndrome (ME/CFS), he investigated patients who’d come down with what appeared to be a mysterious psychiatric disorder. It took him two years but using a new method involving genetic cloning he uncovered the Borna disease virus. It was the first virus discovered using genetic means.

The Borna virus discovery was a game-changer for pathogen community. Jump forward thirty years(after it took the medical community almost three years to find HIV, and viruses are being discovered using molecular means every week. The Center for Infection and Immunity itself discovered 700 new viruses from 2009-2015.

Lipkin was aware of and interested in ME/CFS in the eighties but there was no money. In 1999 he and Britta Evangaard found no evidence of the Borna disease virus in ME/CFS. From there we jump forward to 2010 when NIH Director Francis Collins tasked Lipkin to determine if a retrovirus, XMRV, was causing ME/CFS. XMRV turned out to be a laboratory artifact, and the paper was retracted – something Lipkin said was not all that unusual in science. (He emphasized that he and Dr. Peterson were very careful to put out studies that would stand the test of time.)

The XMRV discovery tanked but proved to be a boon for ME/CFS by heightening the attention around it. Lipkin had kept an eye on ME/CFS for years and after being hired by the Chronic Fatigue Initiative to take it on, he was back in a big way.

In the next portion of his talk he turned to viruses and humans.

Viruses and Humans

How are most viruses getting into humans? From animals. After it’s jump from primates to humans, HIV is, of course, the most familiar example, but viruses are also escaping from bats, birds, pigs, rodents, insects and even camels into humans.

A sea change in the viral field occurred in 1999 when a mosquito-borne virus – the West Nile Virus – had the audacity to attack the residents of the New York City. Lipkin shifted his work from the West to East coasts to search for the virus and ultimately identified it. As the outbreak spread, it got the attention of Senator Joesph Lieberman who sponsored the first big initiative to learn how viruses spread from animals to humans. Politicians, Lipkin noted, can be important allies.

Infections

Most pathogens have yet to be identified by humans.

New York City may be an ideal transit stop for new viruses. Twenty-one million passengers traveling to and from 72 countries pass through New York city airports every year. Animal products including bushmeat – all potentially contaminated with nasty viruses – pour into New York City regularly.

Many more viruses are undiscovered than have been discovered. A survey of one species of bats found fifty-five viruses, fifty of which were new to science. Lipkin estimated 320,000 viruses were still unknown and they’re bumping up against humans all the time. Lipkin next demonstrated how quickly they can jump from animals into humans.

Bats –  Called to investigate an ill Saudi Arabian man (with four wives), he uncovered a new virus called MERS (Middle East Respiratory Syndrome) similar to those found in bats. (Asked if there were any bats in the area, he was told no. The next video showed bats flying every which way in the area :)). If the bats weren’t biting the humans, though, how was the bat virus jumping into people?

Lipkin found MERS was present in about 75% of the camels in the country. Further research indicated that MERS jumped into camels in the 1990’s, and then rapidly escaped into humans around 2010.

MERS

Since its escape into humans around 2010 MERS has spread to 26 countries.

MERS is not particularly easy to transmit but once it gets transmitted, watch out. Death rates are high. It took just one Saudi Arabian to spread MERS to South Korea this year where it killed several dozen people, put several thousand others into quarantine and basically threw the country into a panic. Schools were closed, tourists stopped coming, and parts of the economy slumped as South Korea fought off the virus. It has since been found in 26 countries. It’s the kind of virus that keeps public health officials up at night.

It’s not surprising that Lipkin is wary of pathogens. He noted that he rarely shakes hands but darting a glance at Dr. Peterson said he’d made an exception that evening.

(If you haven’t seen Steven Soderbergh film “Contagion” and can handle apocalyptic scenario’s you might want to give it a try. Lipkin consulted extensively on the movie which involved a worst-case scenario of a virus wiping out much of humanity. The film was praised for its scientific accuracy. (Spoiler alert – we do survive in the end :)).

Ticks –  Coming closer to home Lipkin believes chronic Lyme patients who are not recovering from antibiotics may have gotten another infection from the ticks. He found that over 70% of the Ixodes scapularis ticks associated with Lyme disease carried at least one pathogen and 30% carried more than one in New York. Last year he identified a rhabdovirus (Long Island tick rhabdovirus) new not just to ticks but to science itself. A small survey suggested that 15% of residents may carry antibodies to the virus.

Rats– Lipkin’s  study of New York City’s second most common resident – rats – revealed they carried an amazing array of pathogens including Escherichia coli, Clostridium difficile, and Salmonella enterica, Bartonella spp., Streptobacillus moniliformis, Leptospira interrogans, and Seoul hantavirus.

In one of his many asides (did you know he loves Sinatra?) Lipkin referred to the hamburger and French fries lunch that he and Peterson  usually have. (“Do as we say not as we do” he said). How does Lipkin reportedly like his meat? “Burn it” he tells the waiter. The man is taking no chances – he knows too much.

Infection and Disease

timing-infections-lipkin

The timing of an infection is just one of many factors that determine the effects it will have.

A pathogen is just one of the players, however, in a vast swirl of factors which ultimately determines whether one is going to have a chronic illness. Timing, for instance, is a key factor.

If you expose a mouse to a pathogen at one stage of pregnancy, it’ll stop moving around its cage. If you expose the same mouse to the same pathogen later in pregnancy, it will run round and around its cage unceasingly.

A large autism study underscored the complex role timing plays in humans. The 120,000 person autism birth cohort study found that if a mother comes down with a fever after the first trimester, her chances of giving birth to a son with autism go up three-fold.  If she treats the fever with acetaminophen, her chances of giving birth to an autistic child drop significantly.  If she takes acetaminophen for any other problem than a fever, her risk of giving birth to an autistic child goes up again.

Three to Five Years – An ME/CFS Timeline

How does all this relate to ME/CFS? Likpin cited the findings of their work to date.

  • The suspected pathogens don’t appear to be the problem (the CII is reportedly looking further at herpesviruses.)
  • Evidence suggests altered microbiomes (gut flora) are present
  • Striking differences in immune expression between shorter and longer duration patients suggest profound immune changes have occurred
  • Preliminary evidence suggests that levels “X” and “Y” metabolites and, at least, one immune protein are significantly altered in ME/CFS. (Lipkin embargoed this information pending publication of the paper. One of them is a shocker.)

Lipkin emphasized, though, that ME/CFS is not a one-size fits all disease. For instance, it’s possible that fungi may be a problem for some patients. That’s an intriguing idea given the recent fungi funding in Alzheimer’s disease published in Nature.

Lipkin timeline chronic fatigue syndrome

Lipkin’s timeline for solving ME/CFS given enough resources – a mere three to five years.

Then Lipkin made his bold declaration “We’re going to solve this in three to five years”. It came with a significant proviso “provided the resources are made available” but indicated that he believes ME/CFS is a mystery that can be cracked fairly quickly.  That sounds really fast, but Lipkin’s time-frame is not that far off from Ronald Davis’s 5-10 year time-frame (provided he gets the resources as well.) (or Dr. Montoya’s).

These eminent researchers believe that given the technology present today we could understand ME/CFS fairly quickly – if enough resources were brought to bear.  Lipkin pointed to a slate of researchers in his lab working on ME/CFS to signify the major shift he’s seen happen in just the last couple of years. He said “I couldn’t have gotten them five years ago”.

He highlighted two places the patient community can make an impact:

  • Funding Pilot Studies –   The community can fund pilot studies which can be turned into big grants
  • Advocacy – Lipkin is a savvy researcher. He knows how the NIH works, and once again he emphasized the need for the ME/CFS community to push harder legislatively – to talk to their representatives in the House of Representatives, in particular – and get them to push the NIH for more funding.

Lipkin’s Bucket List

Ian Lipkin has clearly developed a special relationship with ME/CFS, Dr. Peterson, the Simmaron Research Institute. He hadn’t been in the Lake Tahoe area for decades, yet he and two of his assistants had flown across the country to support the Simmaron Research Institute’s spinal fluid work. He was even shaking hands.

lipkin bucket list chronic fatigue

Lipkin’s Bucket List contains two items: solving ME/CFS is one of them.

I shook my head – not for the first time – about Ian Lipkin. How had we gotten so lucky? Lipkin oversees the work of 65 researchers in the U.S. and 150 more across the globe. The New York Times reported that on any given day his lab had 140 viral research projects underway. The head of the National Institute of Allergy and Infectious Disease, Anthony Fauci said, “Lipkin really stands out from the crowd.”

Yet, here he was in the Lake Tahoe area in mid-December exhorting the audience to support an important Simmaron study that he believed needed funding.

What had driven the “The World’s Most Celebrated Virus Hunter” to take on our disease? I asked his assistants. They told me that Ian Lipkin wants to do two things more than anything else before he retires: he wants to solve ME/CFS, and he wants to solve autism. We’re on his bucket list.

That floored me even more (:)) so I asked – but, but…..doesn’t  he care what other people think about this neglected disease? That question left them almost gasping for breath. After they had been able to calm down, they assured me: no Ian Lipkin doesn’t care.

The Simmaron Research Foundation’s Next Spinal Fluid Study

Lipkin was at the event to support the Simmaron Research Institute’s next spinal fluid study. The results of the first one – the most extensive spinal fluid study ever done in ME/CFS – were eye-opening. Using Dr. Peterson’s suggestion to separate atypical from typical ME/CFS patients, and focusing on patients with a longer duration illness, they’d found evidence of an immune dysregulation almost equal to that found in MS. The difference was that instead of being raised, the cytokine levels were reduced in ME/CFS.

That finding surely left a big smile on Lipkin’s and Hornig’s faces.  Earlier they’d found evidence of a profound reduction in immune functioning in the blood of later-duration ME/CFS patients.  Now a similar reduction was showing up in their spinal fluid. These unprecedented findings suggested they were uncovering system-wide problems.

No wonder Lipkin was eager to begin a new and larger spinal fluid study: it’s part of achieving his bucket list.

SR_Donate_6.9.14_1

Triple Your Support! – Between now and Dec 31 triple your support for Ian Lipkin’s work with the Simmaron Research Foundation (SRF). A generous donor is offering to match $2 for every $1 donated before Dec 31. The funds will support the SRF’s collaborations with Drs. Ian Lipkin and Mady Hornig at Columbia University.

 

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

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

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

Mady Hornig

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

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

Immune Exhaustion

collaboration

The blood and spinal fluid findings matched

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

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

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

The Peterson Subsets

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

subsets ME/CFS

Finding subsets was crucial to the success of both studies

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

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

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

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

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

The Gut Work

gut chronic fatigue syndrome

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

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

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

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

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

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

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

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

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

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

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

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

April 3, 2015

“Our results indicate a markedly disturbed immune signature in the CSF of ME/CFS subjects that is consistent with immune activation in the CNS.”

Dr. Mady Hornig, Director of Translation Research, Columbia University

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

Columbia University just published groundbreaking results of the first spinal fluid study to compare ME/CFS with Multiple Sclerosis and healthy controls. For almost his entire career treating CFS patients, Dr. Daniel Peterson has been working toward this day.

Simmaron Research, founded by Dr. Peterson, was a key collaborator in this study, along with Konstance Knox Ph.D. of Coppe Healthcare. Drs. Peterson and Knox provided the spinal fluid samples, and Simmaron’s Research Manager Gunnar Gottschalk did clinical coordination. Drs. Mady Hornig (lead author) and Ian Lipkin (senior author), who run Columbia’s Center for Infection and Immunity, designed the study and led the sample and data analyses. Many thanks are due all the collaborators and especially  the Chronic Fatigue Initiative and Evans Foundation for funding this novel work.

Molecular Psychiatry. 2015 Mar 31. doi: 10.1038/mp.2015.29. [Epub ahead of print]Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Hornig M1, Gottschalk G2, Peterson DL2, Knox KK3, Schultz AF4, Eddy ML4, Che X4, Lipkin WI5.

Cerebral spinal fluid is a colorless fluid that surrounds and cushions the brain and spine. Constantly being produced and absorbed it is fully replaced about four times a day. It provides immunological protection and removes metabolic wastes from the brain.

Lumbar punctures such as those used in this study are primarily used to diagnose neurological disorders.

cerebral spinal fluid

Cerebral spinal fluid protects and removes metabolic wastes from the brain

In several ways, this study distinguished itself from other spinal fluid studies in chronic fatigue syndrome. It examined a more comprehensive cytokine panel (n=51), did more sophisticated statistical analyses (logistic regression/network analysis) and included a multiple sclerosis group as a control. With ninety-one subjects, it was a large sample size for a spinal fluid study (32 ME/CFS patients, 40 MS patients, 19 controls) and it was suitably complex.

Highly Significant Results

Major differences were found. With all the central nervous system problems present in MS, we expect MS would be different from healthy controls. The levels of over half of the cytokines tested (26/51) in the MS group vs the controls were significantly different. An almost equal degree of difference, however, also occurred in the ME/CFS group. Almost half the immune factors tested (23/51) were significantly different in the ME/CFS patients relative to the healthy controls.

Highly significant differences in immune factor levels (p<.0003 or less) were found in 13 cytokines in MS group vs healthy controls, in 4 cytokines in ME/CFS vs healthy controls, and in 8 cytokines comparing ME/CFS to MS.

Immune Exhaustion

reduced immune factors in chronic fatigue syndrome

Most immune molecules were lower in both the ME/CFS and MS patients

The immune system is a complex place. Cytokines have a role in both producing and controlling inflammation. Some evidence points to ME/CFS being an inflammatory disorder, and there’s no doubt that multiple sclerosis is an inflammatory disorder. Interestingly, the cytokine levels in the MS  patients spinal fluid were even lower than those in the ME/CFS patients.

In general both MS patients and ME/CFS trended in the same direction – mostly reduced cytokine levels relative to the controls – but the immune dysregulation was very different. With twenty-three immune factors differing between the ME/CFS and MS patients, a case could be made that the ME/CFS and MS groups differed the most immunologically. The researchers stated ME/CFS patients demonstrated a “markedly greater degree of CNS immune activation” than the MS group.

People in the current study had had chronic fatigue syndrome for about seven years. The relatively low cytokine levels found parallel those found in the longer duration patients in the large blood cytokine study the Columbia researchers recently completed.

“I think what we’re seeing is an immune system exhaustion over time,” Dr. Hornig speculated in HealthDay.

Chemokines, Infections and CNS Damage

Scientists at Columbia … identified a unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that provides insights into the basis for cognitive dysfunction—frequently described by patients as “brain fog”

Chemokines are of special interest in neuroinflammation because these very small proteins regulate immune cell entry into the brain. When an infection occurs, they draw immune cells into the brain by increasing the permeability of the brain blood barrier. The microglia and astrocytes are the primary chemokine producers in the brain.

Infection or demyelination possible in ME/CFS

High CXCL10 levels have been associated with infection or demyelination

Two chemokines (CCL11 and CXCL10) were increased in both the MS and ME/CFS groups with much higher levels of both found in the MS group.

CXCL10 clears the way for the entry of natural killer cells and T lymphocytes into the brain. It is often prominently expressed in the CNS in response to viral infection.

As always the immune system walks a fine line. Too little chemokine expression and a deadly infection can take root. Too much chemokine expression and brain damage and seizures can result. While CXCL10 plays an important role in combating viral infections, excessive CXCL10 levels can cause neuron die off and trigger a immune-mediated demyelinating disease.

Demyelination is a major problem in MS but is only a possibility at this point in ME/CFS. A small recent Stanford study suggested myelin abnormalities along with white matter atrophy may be present in ME/CFS. .

Not surprisingly, CXLC10 clearly has an impact on symptoms. Neutralizing CXCL10 even during a persistent infection can greatly reduce symptom severity.

Allergic Response, Eotaxin and Brain Fog

“These immune findings may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog.” Dr. Mady Hornig

IL1ra is supposed to tamp down an allergic response as well. The network analysis in this study suggests that it’s not working so well in ME/CFS patients. The inverse relationship between IL1ra and CSF2 (GMCSF) levels in the ME/CFS patients, indeed, suggested an allergic response was underway. Reduced CSF2 levels were found in a prior ME/CFS spinal fluid study as well.

Then there is eotaxin (CCLII). Eotaxin recruits white blood cells called eosinophils that are involved in producing an allergic response in the brain. The logistic regression suggested increased levels of eotaxin (and decreased levels of IL1b) are highly associated with “ME/CFS caseness”.

eotaxin chronic fatigue syndrome

Eotaxin has been associated with cognitive declines and reduced neuron growth in mice.

Eotaxin is not a chemokine one particularly wants to have around. Increased eotaxin levels have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age. Introducing eotaxin into the CNS of young mice reduces neuron production. (At the last IACFS/ME Conference, the CDC reported reduced telomere length – another possible sign of increased aging – was present in ME/CFS.)

“…we now identify systemic immune-related factors (eotaxin) as potentially critical contributors to the susceptibility of the aging brain to cognitive impairments”. Villeda et. al. 2011 – From a mouse study published in Nature

One doesn’t think of allergy in terms of the central nervous system, but the authors reported that allergic processes could be indicative of a central nervous system infection. The chemokines upregulated in the ME/CFS patient’s spinal fluid have been associated with microglial activation and central nervous system infections.As the publication notes, “Persistent secretion of cytokines by activated microglia, brain immune cells of macrophage-monocyte lineage, may contribute to this pattern.”

Networks Awry

“The inverse relationship we found between IL1ra and CSF2 in the CSF of cases using a network analysis approach suggests that neuroimmune responses may be shifted toward allergic or Th2 (autoimmune) patterns in the CNS of individuals with ME/CFS.”

The Hornig/Lipkin team also found evidence of disturbed “networking” in ME/CFS; i.e. immune cells communicating strangely. IL-1ra is an interleukin that prevents cells with IL-1 receptors from producing the powerful pro-inflammatory cytokines IL-1A or IL-1B. It stops that part of the immune response in its tracks, but the network analysis suggested it wasn’t doing that in ME/CFS.

Summing Up

  1.  The fact that the alterations in the immune factors in the ME/CFS were almost as extreme as in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction –  suggests a major pathology is present in the central nervous systems of ME/CFS patients.
  2. The low cytokine levels suggest that some sort of immune exhaustion –  caused by an infection or by immune upregulation – is present in ME/CFS.  These findings parallel those of the recent Hornig/Lipkin study suggesting that  immune up regulation early in the disorder may lead to immune burnout later on.
  3. Several of the immune factors in the ME/CFS patients spinal fluid suggest an allergic type of reaction may be occurring in their CNS. A similar finding is also found in some central nervous system infections; i.e. an infection could be driving this process.
  4. The immune factor most identified with the ME/CFS patients has been associated with cognitive declines, aging and reduced neuron production.

Moving Forward

“Diagnosis of ME/CFS is now based on clinical criteria. Our findings offer the hope of objective diagnostic tests for disease as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with ME/CFS at different stages of their disease,” adds W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the Center for Infection and Immunity.

Daniel Peterson

Dr. Daniel Peterson

Early on, MS didn’t have biomarkers or diagnostic tests, and it had skeptics like CFS does. Later it was diagnosed by specific proteins in spinal fluid. Now there are FDA-approved treatments.

ME/CFS patients often have central nervous system symptoms, like cognitive dysfunction, balance problems, and nerve and pain issues. Those symptoms convinced Dr. Peterson many years ago that spinal fluid may hold the key to understanding the disease. His perseverance helped make this study possible.

Columbia University’s press release stated:

“There is precedent for use of human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis. However, the researchers note, additional work will be needed to assess the safety and efficacy of this approach.”

We need more research to translate these unprecedented findings into diagnostics and treatments.

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Major Study Suggests Early Immune Activation May Drive Chronic Fatigue Syndrome

“This study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease” W. Ian Lipkin

big me-cfs study

Big study – big results

Distinct plasma immune signatures in ME/CFS are present early in the illness. Hornig. M. Monotoya, J, Levine, S., Felsenstein, D., Bateman, L, Gottshalk, G….Likpin. L. Sci Adv 27 Feb. 2015.

It’s a major study indeed – the first, I believe, to come out of the Hutchins Foundation’s Chronic Fatigue Initiative and the media is picking it up quickly. The Hutchins Foundation doesn’t mess around. They’re putting $10 million into researching chronic fatigue syndrome. They do big rigorous studies with top researchers.

This study with its carefully selected patients from across the country was loaded with ME/CFS expertise. Besides Mady Hornig and Ian Lipkin of Columbia, Dr. Montoya, Dr. Peterson, Dr. Klimas, Dr. Bateman, Dr. Levine and Dr. Komaroff were listed as co-authors.

The Simmaron Research Foundation and Dr. Peterson provided samples for this study. One of  Simmaron goals is to provide samples and data from well-characterized patients to major researchers and institutions.

It’s Biological

“These immune signatures represent the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages.” Columbia University Press Release

Once again we see claims made that finally, finally we have proof that ME/CFS is a biological illness. (The head of the CDC said something similar regarding their study about ten years ago at a National Press Club event.) This time the claim is a bit different, however. This time they have not just evidence but “robust” evidence that ME/CFS is a biological illness.

If the study size is any indicator of robustness – and in a well-designed study it is – their evidence is robust, indeed.

Big, Big, Big Study

This wasn’t just a big study – it was a huge study containing almost 650 patients and healthy controls (298 ME/CFS patients and 348 healthy controls).  (A similarly large study is underway at Stanford).

All the patients met both the Fukuda and Canadian Consensus Criteria.

The study wasn’t just big in size – the 51 immune factors it measured meant it was deep as well, and  leptin was one of the immune factors measured.

Different But Not Substantive

The study started off on a bit of a downer. Differences in immune factors between the ME/CFS patients and the healthy controls were present, but not “substantive”.

Note, however, almost all the immune factors are lowered – not increased –  in the chronic fatigue syndrome patients. We’ll come to a reason for that later.

  •  Pro-inflammatory – IL171A (p<.0043), CXLC10 (p<.04), TNF-B (p<.0028), Il-6 (p<.04), sFasL (p<.01)
  •  Anti-inflammatory – Il-10 (p<.024), CSF1 (p<.025)

The one immune factor moderately  increased in ME/CFS was leptin (p<.03).

That didn’t mean many in the group hadn’t experienced profound immune alterations, though. They had – earlier…

Hit and Run Attack Likely

“The immunopathology of ME/CFS is not static” the authors.

Further analyses uncovered something the authors freely admitted surprised them. The ME/CFS patient’s immune measures didn’t differ by triggering factor or age or even by sex – they differed by time.

chronic fatigue syndrome early immune findings

The key factor for the immune system – was time

Alterations in over half the immune measures found (combined with some very, very low probability factors that the results weren’t correct)  (p< >0002-.0008) indicated that “substantive” differences in immune functioning had existed at one point in time.  The short duration patients showed signs of intense immune activation not found in the other groups.

Both the pro and anti-inflammatory sides of the immune system were on high alert early on in ME/CFS.

Immune Differences Between Short-term ME/CFS patients and Healthy Controls:

  • • Increased levels in ME/CFS: IL1A, IL1B, IL-6, IL-12, IL-17a, Il-17f, IL-8, TNF-a, sFasL, TRAIL, IFN-y, CCL2, TGFa, CSF, resistin, CCL-11, CSF2, IL1RA, IL-13.
    • Reduced Levels in ME/CFS – PDGFBB, CD40L

Cytokine results have been spotty in ME/CFS and that’s been a problem.   A few up or down regulated cytokines just don’t raise many eyebrows in the research world. They’re looking for evidence of broad immune alteration – and here it is. I don’t think anybody has seen this kind of sweeping immune activation in ME/CFS before.

Viral Fighter Stands Out

A logistic regression suggested that IFN-y played a particularly significant role in the immune system activation. Produced mostly by natural killer and cytotoxic T-cells – two cells with similar problems in ME/CFS – IFN-y is both an immune stimulator and pathogen inhibitor. (Microglia are big IFN-y producers in the central nervous system).

The IFN-y findings suggest either a pathogen attack or an autoimmune shift may be triggering the immune upregulation seen early in the disease.

infection chronic fatigue syndrome

Bug alert! The early immune findings were consonant with a pathogen attack.

High IFN-y levels are associated with Th2 dominance in the immune system and an increased risk of autoimmune processes. Post-viral fatigue has been associated with high IFN-y levels, and alterations in the IFN-y gene have been associated with increased fatigue following infection as well.

IFN-y also showed up in Broderick’s small study examining 16 cytokine levels in adolescents in the first two years after coming down with infectious mononucleosis. Four cytokines IL-8, Il-23, IL-5 and IL-2 were significantly altered or nearly significantly altered.

IFN-y levels were not increased but a computer model suggested it and four other cytokines constituted an immune signature that differentiated people who came down with ME/FS after IM and those who recovered.

Mady Hornig on the Study

IL-5 levels were significantly decreased in ME/CFS patients but IL-5 did not, interestingly enough, make it into the computer model. Further analysis indicated that IL-5 levels were significantly correlated with Il-23 and IFN-y: two cytokines that did make into the model. These cytokines were essentially analogues for IL-5 in the body.

THE Pathway???

IFN-y also accelerates tryptophan degradation by activating the indoleamine-2,3 deoxygenase enzyme in the kynurenine pathway – Mady Hornig’s favorite pathway. That pathway produces neurotoxic substances that increase production of the excitatory neurotransmitter glutamate that some researchers believe is in play in both fibromyalgia and ME/CFS. Andrew Miller of Emory University has earmarked the kynurenine pathway in ME/CFS.

kynurenine pathway chronic fatigue

Could the kynurenine pathway be it for ME/CFS?

Cognitive problems and mood changes have been associated with up-r egulation of the kynurenine pathway in diseases ranging from Alzheimer’s to depression. In fact, disruption of the one part or other of the kynurenine pathway occurs in many neurological and psychological disorders.

The authors were confident enough to hypothesize that lesions produced by high IFN-y levels early in the disease are producing the cognitive slowing and depression found in ME/CFS. Andrew Lloyd of the Dubbo project has been suggesting for years that high cytokine loads early in the disease process had disrupted brain functioning, but nobody has gotten this specific before. Now Hornig and Lipkin et. al are proposing a specific mechanism for that: IFN-y produced lesions.

“We propose that IFN-y mediated lesions in kynurenine metabolism may culminate in the depression and psychomotor tardiness (slowed information processing) that contribute to disability in some patients with ME/CFS”.

That kynurenine pathway gets more intriguing when we consider that IFN-y activation and tryptophan degradation has been associated with chronic Epstein-Barr virus infection. Epstein-Barr virus is often associated with infectious mononucleosis – a common trigger of ME/CFS.

CD40L

CD40L appears to be another early key immune factor. A clear driver of immune functioning in the healthy controls and longer-term ME/CFS patients, CD40l was found to be reduced and strangely disengaged from the immune system in shorter-term ME/CFS patients.

A B-cell maturation regulator, deficiencies in CD40L are associated with recurrent infections and unexplained cognitive issues and CD40 deficient mice exhibit major immune deficiencies. Citing the Fluge/Mella Rituximab study the authors suggested the collapse of this immune factor   early in this disease could be important.

One scenario proposed by this study – natural killer and cytotoxic T-cells pumping out IFN-y early in the disease only to collapse later on–appears to fill in some holes that smaller studies would have missed. If this study is correct then maybe 20% of the patients in any study have probably had ME/CFS for three years or less. That would mean that the typical low NK dysfunction will show up but the up-regulation early in the disease the authors believe may be contributing to that doesn’t.

Flipping the Switch

That suggests that somewhere around the 3rd year of illness major immune shift occurs. The immune system flips from being hyperactive not to being normal but to being somewhat under active.

Dr. Hornig described a condition of immune system burnout:

“It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop.”

primed for burnout cfs

Does the immune system get burned out in longer duration ME/CFS patients?

There’s something very right about “immune exhaustion” being associated with this disease The fact that many cytokines  increased in the early stages of ME/CFS are  decreased in the later stages suggests a kind of burnout process is occurring.

Poor natural killer cell functioning in ME/CFS is often described as a type of immune system “burnout” and evidence is emerging of similar cytotoxic T-cell problems as well.

Leptin Again

It’s hard for me parse how leptin showed up in this study. The only immune factor increased in the whole ME/CFS group vs the controls, leptin was highlighted in one network analysis of early duration patients and showed up moderately in two others. The authors noted that it was tightly correlated with most of the immune factors later in the disease but not early.

Another cytokine called PDGFBB appeared to be the main driver of the immune reductions later in the disease.

Hit and Run Again

That suggests the disease has in some way moved on from the immune system. The authors of the paper didn’t have a great explanation for why people remained ill after their immune system activation had died down or had become decreased. If Younger’s findings pan out perhaps the lone elevated immune marker – leptin – found is enough.

hit and run me/cfs

The findings suggested ME/CFS is a hit and run disease.

A email to Jarred Younger gave a quick answer  and a warning that it was not based on a close reading of the paper. He suggested systemic inflammation may drive ME/CFS early on but sensitized microglia and astrocytes in the central nervous system drive it in its later stages. Because we don’t have good ways to test central nervous system inflammation at that point the disease mostly becomes invisible to testing afterwards.

In fact, the authors tantalizingly noted because ME/CFS appears at least in part to be a central nervous disorder cerebral spinal fluid may very well be a better medium to investigate than peripheral blood. That could suggest we’re due some more important findings in a couple of weeks when the Simmaron Research Foundation/Chronic Fatigue Initiative CSF study is published.

The High Cytokine- Longer Duration Patients?

The study doesn’t make any mention of longer duration patients ME/CFS patients with high cytokine levels. Anecdotal reports from patients indicate they are definitely out there, but this study – involving many quite ill patients being seen at ME/CFS practitioners – suggests that they probably constitute a relatively small subset of patients.

Conclusion

“We now have evidence confirming what millions of people with this disease already know, that ME/CFS isn’t psychological,” Mady Hornig, MD

This large study presents what appears to be almost novel finding in medicine: distinct before and after stages early in a chronic illness. In the early stages of ME/CFS (first 3 years) a distinct and impressive immune activation is present that is followed by modest immune deactivation.

The early immune activation is highly suggested of an infection or some other immune altering process.

The study may ultimately open up possibilities for treating patients with recent onset but provides no possible treatment options at this point for patients who have been sick longer. The  more modest immune deactivation found later in the disease suggests that the core causes of the disease are either found elsewhere or were not illuminated by the study.

A major question facing researchers now is finding ways to translate this hit and run immune activation or viral infection into long lasting central nervous system problems. Microglia sensitized by chronic immune activation/kynurenine pathway activity is one possible answer.

Ian Lipkin’s statement that they hope to find important answers in their microbiome study suggests he believes a permanently altered microbiome  could provide an answer to that question.

“The question we are trying to address in a parallel microbiome project is what triggers this dysfunction.”Ian Lipkin

The authors statement that cerebral spinal fluid may provide a better medium for understanding this disease could mean we’re in for some interesting findings in a couple of weeks.  The Simmaron Research Foundations rare  and extensive trove of cerebral spinal fluid samples from ME/CFS patients provided the foundation for that study.

Stay tuned!

Simmaron Research Foundation Study Targeting Roots of Immune System Breakdown in Chronic Fatigue Syndrome (ME/CFS)

June 13, 2014

Simmaron Research’s  new immune study builds on exciting research that is changing how we think about ME/CFS.

Twenty years ago  the internationally known virus hunter, Dr. Ian Lipkin of Columbia University, didn’t find Borna Virus in people with ME/CFS, but he never forgot the immune dysfunction he found.  Twenty years later he found more immune dysfunction in another study.

Isabel Barao, PhD, Simmaron Research Scientific Director

Isabel Barao, PhD, the Simmaron Research Foundations Scientific Director believes a genetic predisposition to immune problems could underlie ME/CFS

He doesn’t know why it’s there but he does believe that all ME/CFS cases – no matter what pathogen or other factor has triggered them –  devolve to a ‘common pathway’. The fact that pathogens of all types – from Epstein-Barr Virus, to SARS, to Giardia – can trigger ME/CFS suggests a core immune deficiency lies at the heart of the illness.

Every genetic study suggests an inherited susceptibility to Chronic Fatigue Syndrome is present. Dr. Mady Hornig of the Center for Infection and Immunity at Columbia University believes that a genetic predisposition in combination with an environmental trigger (such as an infection) occurring at just the right (wrong) time is probably key to coming down with ME/CFS.

For thirty or forty years you might be able to easily slough off this bug or that pathogen, but at some point for some reason the stars aligned; you were depleted in just the right way, the pathogen hit and with your immune system genetically predisposed to crack under the pressure – it did – and your entire system faltered.

gene strand

Simmaron is looking for the genetic roots of an immune system breakdown

Simmaron Research’s next pilot study is looking for that immune crack in the dike – the genetic underpinnings of the system collapse that occurred. Led by Simmaron’s Scientific Director, Isabel Barao, PhD, in collaboration with researchers at the National Cancer Institute and University of Nevada Reno, it will determine if your NK and B-cells and macrophages are genetically predisposed to respond poorly to a virus, toxin, or cancer cell.

Dr. Barao is studying whether people with ME/CFS have polymorphisms – unusual gene formations – that make their key immune cells less likely to respond well to viruses and other threats. That immune ‘hole’ many people have talked about with regards to ME/CFS could start here. We all know about the rampant NK cell problems in ME/CFS, but this study could help explain the B-cell problems recently uncovered in a German research study – and perhaps even shed light on why Rituximab may be working in some patients.

It’s the initial part of a projected three-part study that could end with drugs for ME/CFS. Once genetic alterations have been found, they’ll be correlated with immune findings. If that holds up, it’ll  be time to look for drugs to fix the problem, two of which are currently in clinical trials.

We-Have-Ideas

Support the Simmaron Research Foundation as it redefines how ME/CFS is understood and treated

Think about it. The high heritability rates in ME/CFS indicate genetic problems exist somewhere. Where better to look than the immune system?

This study is a no-brainer to me. It’s relatively cheap – it has a quick six-month turnaround – and the data it produces will lay the foundation for an NIH grant on topics they’ve  shown they’re willing to fund.

Help us redefine ME/CFS.  Support breakthrough science on immune deficiencies at Simmaron.

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