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Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, View ORCID ProfilePetter Brodin
doi: https://doi.org/10.1101/2020.02.20.958249
Lucie S.T. Rodriguez
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Christian Pou
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Tadepally Lakshmikanth
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Jingdian Zhang
2Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17176, SWEDEN
3Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, SE-17176, SWEDEN
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Constantin Habimana Mugabo
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Jun Wang
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Jaromir Mikes
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Axel Olin
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Yang Chen
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
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Joanna Rorbach
2Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17176, SWEDEN
3Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, SE-17176, SWEDEN
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Jan-Erik Juto
4Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, SE-17177, SWEDEN
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Tie Qiang Li
4Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, SE-17177, SWEDEN
5Department of Medical Radiation and Nuclear Medicine, Karolinska University Hospital, SWEDEN
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Per Julin
6Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, SE-17176, SWEDEN
7Neurological Rehabilitation Clinic, Stora Sköndal, Sköndal, Sweden, SE-12864, SWEDEN
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Petter Brodin
1Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, SE-17121, SWEDEN
8Unit of Pediatric Rheumatology, Karolinska University Hospital, SE-17176, SWEDEN
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  • ORCID record for Petter Brodin
  • For correspondence: petter.brodin@ki.se
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Abstract

Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection. The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting the vagus nuclei, and higher centers in the brain of ME-patients and induce a sustainable, ∼30% reduction in overall symptom scores after eight weeks of treatment. By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover chronic immune activation in ME, as well as immunological correlates of improvement that center around the IL-17 axis, gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We wish for these results to bring some hope to patients suffering from ME and inspire researchers to help test our new hypothesis that ME is a condition caused by a failure of inducing disease tolerance upon infection and persistent immune activation.

Footnotes

  • We have updated figure 1 to make it clearer and revised some of the text to clarify the conclusions from the current study.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 28, 2020.
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Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin
bioRxiv 2020.02.20.958249; doi: https://doi.org/10.1101/2020.02.20.958249
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Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin
bioRxiv 2020.02.20.958249; doi: https://doi.org/10.1101/2020.02.20.958249

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