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)?
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.[embed]https://www.youtube.com/watch?v=LwOUzE03xm0[/embed]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.
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.
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. Nathhttp://simmaronresearch.com/2019/03/nath-intramural-chronic-fatigue-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.
- Watch the first day videocast here
- Watch the second day videocast here
- I will be tweeting from the Livestream of the conference here.
Learn more about the NIH Conference below.https://www.healthrising.org/blog/2019/02/12/nih-looks-future-chronic-fatigue-syndrome-me-cfs-conference/