Journal
PAIN
Volume 163, Issue 7, Pages E821-E836Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000002498
Keywords
Fibromyalgia; Chronic pain; Widespread pain; Peripheral nerves; Small fiber neuropathy; ULBP; NKG2D; Natural killer cells; Flow cytometry; Skin; Whole blood; RNA; DNA
Categories
Funding
- Canadian Excellence Research Chairs (CERC) program [CERC09]
- Pfizer Canada Professorship in Pain Research, CIHR [SCA-145102]
- Patient-Oriented Research (SPOR) in Chronic Pain, NIH/NIDCR [U01DE017018, 2014_A129]
- European Academy of Neurology (EAN) Clinical Fellowship Programme
- Interdisziplina res Zentrum fur Klinische Forschung (IZKF) [F-N-376]
- European Research Council (ERC) under the Horizon 2020 research and innovation programme [866075]
- Swedish Research Council [542-2013-8373]
- Knut and Alice Wallenberg Foundation
- CIHR postdoctoral fellowship [MFE-171299]
- Central Norway Regional Health Authority
- Norwegian Institute of Public Health
- National Institutes of Health (NIH), University of Michigan
- Norwegian Research council
- Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU)
- Department of public health and nursing, Faculty of medicine and health sciences
- Norwegian University of Science and Technology (NTNU)
- Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
- K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
- HUNT Research Center
- European Research Council (ERC) [866075] Funding Source: European Research Council (ERC)
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The pathophysiology of fibromyalgia syndrome (FMS) is still unknown. This study found that patients with FMS had a decrease in natural killer (NK) cells, which were exhausted yet activated. Genetic and transcriptomic analysis showed enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies also revealed the presence of NK cells near subepidermal nerves in FMS patients.
The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.
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