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'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

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.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

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 very 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.