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East African Disease Informs Nath’s Search for the Cause of ME/CFS

Could a disease found in the remote villages of East Africa end up being a model for chronic fatigue syndrome (ME/CFS)?

Ugandan Village

Ugandan Village (from the NIH)

Dr. Avindra Nath – the leader of the NIH Intramural study on ME/CFS –  thinks perhaps so. He’s not daunted by mysterious diseases and nor should he be. Just a couple of years ago his NIH team was able – by bringing new technology to bear – to unravel a mysterious disease plaguing children in Africa. Using a much larger array of tests he’s hoping to do the same in ME/CFS.

Nath became acquainted with “nodding syndrome” at a meeting in Uganda in 2012. This strange and often devastating disease, found in the remote regions of Uganda, Tanzania and South Sudan, causes children’s heads to periodically nod  and can produce seizures, mild to severe cognitive impairment, muteness, gait problems, paralysis and often death. Brain scans have shown significant brain atrophy.

Studies suggested that the disease was linked to a parasite, Onchocerca volvulus, carried by the black fly, but numerous efforts to find the parasite in the brain or cerebral spinal fluid failed.  Attempts to tie it to immune factors including autoantibodies, as well as genetics, toxins, nutritional factors, and others came to naught as well.

Like ME/CFS the speculation regarding the cause of nodding syndrome has been rife with possible connections to autism spectrum disorder, Alzheimer’s, poor nutrition, PTSD and others being put forth. Ugandan psychiatrists have even proposed that the disease is a form of “Developmental Trauma Disorder” brought on by the war.

Enter Nath, Tory Johnson, a former postdoc fellow of his, and Thomas Nutman, a National Institute of Allergy and Infectious Disease (NIAID) researcher.  Suspecting the problem was autoimmunity, they brought out one of their big guns – a kind of protein chip technology that allowed them to screen for thousands of antibodies at once.

The results were tantalizing. The levels of four antibodies were 100 fold higher in the sick children compared to the healthy children.  Further testing revealed that two of these antibodies were more reactive or active in the sick children. They ended up focusing on one antibody found in both the blood and cerebral spinal fluid.

This antibody – which was linked to the leiomodin-1 protein  – reacted 33,000 times more strongly in the children with nodding syndrome.  Interestingly, both groups – the sick and the healthy children – carried the antibodies, but they were elevated in the sick children.

Leiomodin-1 staining neurons

Staining reveals Leiomodin-1 antibody (green) interacts with human neurons

After finding this link, they deepened their search. The leiomodin-1 protein had been found primarily in smooth muscle tissue and the thyroid, but if it was causing the neurodegenerative symptoms it had to be in the brain as well. Further testing, including immunostaining human neurons, indicated that protein was indeed found in parts of the brain imaging studies had indicated were associated with nodding syndrome.

Having established a putative link between the antibody and the disease (that it was found in and could potentially affect the brain) the next step was to demonstrate that the antibody could indeed be causing the disease. Subjecting cultured human neurons to the antibody showed that the antibodies could indeed be damaging the childrens’ neurons.

Getting at the source of the antibody was next. The authors hypothesized that an immune attack against the parasitic worm had gone awry and was attacking the ill childrens’ neurons. This could only happen, though, if the parasitic worm and human neurons shared genetic sequences that could cause the immune system to mistakenly attack human neurons. Studies confirmed that a very short sequence of the parasite’s tropomyosin gene was quite similar to a sequence expressed in human neurons.

autoimmune responses ME/CFS

Nath believes the infections may have triggered a variety of autoimmune responses targeting the brain in ME/CFS

With that, the circle was closed. They had identified an antibody, shown it was in the brains of the sick children, showed that it could do damage to the neurons that were damaged in the children, and demonstrated similar genetic sequences were present in the parasite and humans.

There was still the nagging issue of antibody prevalence, though.  Only slightly over 50% of the sick children had antibodies to leiomodin-1. If the antibody to leiomodin-1 was causing the disease in these children, what was causing the disease in the others?

Nath et al proposed that the parasite triggers a different immune response in different children.  Some of the children developed autoantibodies that damaged neurons in their CNS  – and produced nodding syndrome (which is now understood to be a form of autoimmune epilepsy).

This syndrome is likely not a disease mediated by a single immune specificity. We speculate that nodding syndrome may not be a single antibody syndrome.  Nath et al.

Citing test results which showed a range of elevated autoantibodies in the sick children, they suggested that some children with nodding syndrome have developed antibodies to  neuronal proteins other than leiomodin-1.

A Model for Chronic Fatigue Syndrome (ME/CFS)?

Nath reported that his approach to ME/CFS has been shaped by his experiences with nodding syndrome. He suspects the infectious onset that so many people with this disease experienced triggered their immune system to accidentally produce autoantibodies that are attacking their central nervous system or other parts of the body.

If suspect antibodies show up, future research efforts will presumably proceed down the same pathway as they did in Nodding Disease: first they will identify the proteins the antibodies are attacking, and then they will determine where those proteins are found, and demonstrate experimentally that the antibodies are likely doing damage.

Nath and his compatriots uncovered the antibody connection to nodding disease seven years ago – a long time in this age of fast moving medical technology. Nath reported he’ll be using a newer approach involving mass spectrometry, or phage display, in ME/CFS which will allow him to “probe almost infinite numbers of proteins/peptides”.

Seven years ago, extensive testing had failed to find a culprit leaving the cause of nodding syndrome a complete mystery. In 2017 Nath et. al. produced a clear pathway that explains about 50% of nodding syndrome victims.

Technology Paves the Way

Note that the breakthrough didn’t come from the slow accumulation of results over decades; –  it occurred very quickly and simply required the right technology being applied to the disease. When that happened, a cause of the disease became clear, and researchers simply proceeded down established pathways to prove  it.

Nath and the NIH are looking at much more than antibodies in their intramural study, and ME/CFS, with its multiplicity of triggers, is likely to be more complex than nodding syndrome. The same principle, though, – a variety of autoimmune processes produced by an infectious trigger – may apply.

Dr. Nath appears to have gotten at a cause of one mysterious disease. May he be as successful with this one.

Check out an interview with Dr. Nath

Dr Nath Talks on the ME/CFS NIH Intramural Study

The NIH’s Accelerating Research on ME/CFS Conference

Because of a death in the family, Brian Wallitt will be presenting in Dr. Nath’s place at the NIH conference. Dr. Nath reported that Wallit will present on the high rate of rare diseases found during the first half of the study and some other data but will not present statistical analyses. With just half of the projected participants having finished the first part of a two-part study, the lack of statistical analyses is not really a surprise.

Brian Wallitt will be presenting at 10:00 AM EST on April 5th (day two) of the Accelerating Research on ME/CFS conference – the first NIH sponsored research conference on the disease since 2011. Check out the agenda here.

Learn more about the NIH Conference below.

NIH Brings in New Faces and Looks to the Future in Accelerating ME/CFS Research Conference

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    April 2, 2019 at 7:46 pm - Reply

    Well that explains a lot. While I too believe CFS is primarily a CNS disease, ie.,. crashes, PEM, brain fog, I have never met a Neurologist that truly believes in it as a “disease.” I believe they all feel the person has either not been worked up properly (has a rare disease) or has a neurological disease that has just not been “discovered” yet.

  • Tim Foley

    April 2, 2019 at 8:14 pm - Reply

    I love this report. First it explains how some pathogen can hide from detection and gives a path forward to identify if CFS is from a simple pathogen or a combination of pathogens. The chip based diagnostic tools need to be used more. I think Roche is developing these. Thank you.

  • dejurgen

    April 2, 2019 at 8:45 pm - Reply

    That is some very fine research Dr. Nath has done there!!! My respect for the doctor skyrockets upwards. I may have been prejudged before as he works at the NIH and the relations between the NIH and the ME/CFS community aren’t always that warm.

  • konijn

    April 2, 2019 at 11:07 pm - Reply

    great job he has done! I only wished the number of patients where higher than 40 for the intramural studie on me/cfs and not limited like only 5 years of illnes and not only the infectoius desese onset group. now it feels like it wil take decades and decades and I am allready decaedes severely ill and getting worse.

  • Cort Johnson

    April 2, 2019 at 11:08 pm - Reply

    There is bureaucracy at the NIH and then there are researchers. Collins certainly seems to hvae picked the right guy to do this study. Hopefully, Nath’s work will provide insights that enroll them in spending time with ME/CFS. That’s the goal of the study – let it be so!

  • Cort Johnson

    April 2, 2019 at 11:11 pm - Reply

    Yes, I wish the number of patients was higher as well. (Abd I wish the study was going faster! ) Nath did say that he thinks he can pick up evidence of subsets from that number and he has said that if it looks like need to expand the study he can (within reason).

    I think the restrictions will allow Nath to hone in as quickly as possible on ME/CFS and then translate the results to the rest of us who have been waiting for so long. I think its the quickest way given the funding – which we all believe should be greatly increased.

  • Cort Johnson

    April 2, 2019 at 11:13 pm - Reply

    I guess that’s how Ugandan researchers end up positing that nodding syndrome is some sort of trauma disorder. It seems that medicine has this tendency to go to the trauma or behavioral side when they can’t figure something out. Thankfully for nodding syndrome and hopefully for ME/CFS Nath is taking a different tack.

  • Joan McVichie

    April 2, 2019 at 11:44 pm - Reply

    I have been reading all the research for years, and I stand to be corrected, but has anyone researched the changes to our food?? I am speaking about the genetic engineered food that has been put out for years now, & the glyphosate that is added to all food for human, & animal consumption, except organic food, & even it shows some results of pesticides. Even breast milk tests are positive for glyphosate. Has anyone tested that our bodies are reacting to all the chemicals in our food, water & air?

  • Patrick

    April 3, 2019 at 7:23 am - Reply

    My brother is a top-tier researcher and physician and I asked him what some of the latest research in his field (Infertility) and he mentioned that epigentics seems to be the answer (not drugs, not in-vitro fertilization etc). The issue is that the change in epigentics is likely due environmental toxins.

    I have made strides in recovery using detoxification methods.

  • sophie

    April 3, 2019 at 11:41 am - Reply

    I don’t nod but have a tendency to shake my head, which cóuld be related to PACE-trial- and other shenanigans 😉 but I think it’s a neuro thing

  • Aidan

    April 3, 2019 at 1:58 pm - Reply

    I just recently did the Panoramic x-ray at my Dentist Office it is now showing possible Eagle Syndrome both sides I cannot see the full styloid process but the right side is very pointy, long &

    the left side is thick, long & pointy it does not seem to go under into my jaw but still hard to see it all…I will know more once a CT Contrast is done of Brain/Neck areas & hopefully I can also

    get it in 3D as well…Some who have had proper Surgeries are back to100% normals their illness lifted…Some took long to heal some say day felt relief after Surgery providing nerve damage do not occur

  • Aidan

    April 3, 2019 at 2:01 pm - Reply

    Those items you had mentioned were not around in the 1930s & if ME/CFS is another name for EDS types it was recorded that EDS was known back in the 12th Century in the Medical Literature…

  • David

    April 3, 2019 at 2:29 pm - Reply

    No real treatment or cure for Nodding Syndrome though… Hope it won’t be the same for us when cause eventually found

    • Cort Johnson

      April 3, 2019 at 3:05 pm - Reply

      There’s no easy fix but the Nath paper recommended immune treatments. If some people with ME/CFS have an autoimmune process going on then anti-monoclonal antibody drugs will presumably be a possibility. As this is a huge growth area in drugs, I assume that they’re getting more effective all the times. Time will tell.

  • Robert Wolfe

    April 8, 2019 at 12:02 am - Reply

    Spiroplasma! Spiroplasma from monanema martini! NIH is overlooking them!

  • Robert Wolfe

    April 8, 2019 at 3:03 pm - Reply

    Vaccination status? There’s a difference in the older ones who can live with the parasites, and the youth, who contract the syndrome. In time, the adults will get the syndrome too, but not until they get older. You might wonder how I know this? Because my father died of it, and because I have it too! Been nodding since my preteens, and came close to going like dad! Horsefly bites and cleaning squirrels barehanded is how we got them!, But we have a parasitology division ran by a pompous ass who wishes to go on with the dogma, they don’t exist here! M. martini, spiroplasma, both are here and have been here for eons. Work on it, even if you have to find a way to work around said pompous ass, who shall remain unnamed! My dad would likely still be alive had said ass listened me! Further, I see it in many of my squirrel cleaning relatives! Spiroplasma, and likely the helminths they are associated with is also the cause of CWD in deer! I’ll work on educating hunters, you folks work on proving things!