Both central and peripheral nervous systems have been shown to be affected in fibromyalgia (FMS).
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[Genetic] sequencing and proteome-wide studies have identified molecular signatures consistent with low-grade chronic inflammation in patients with FMS.
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To further our understanding of the immune system’s involvement in FMS, here, we aimed to identify immunophenotypic differences between individuals with and without FMS in a hypothesis-free manner.
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The Canadian cohort: Forty-four patients with FMS and 46 matched controls were deemed sufficient to reject the null hypothesis. [...] The German cohort: 117 women (median age of 52 years, range: 22- 75 years) with FMS were enrolled at the Department of Neurology, University of Wuerzburg, Germany.
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The Fibromyalgia Survey Questionnaire (FSQ) that assesses the key symptoms of FMS was also administrated, and FSQ severity score was calculated.
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Skin punch biopsies measuring 6 mm were obtained from the right lateral lower leg and upper thigh of the German cohort participants. The skin punch biopsies obtained from the lower legs of 17 patients with FMS and 11 controls were randomly selected for this study.
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Among all the [blood immune cells in the Canadian cohort], NK cell subsets were best able to differentiate FMS cases and controls. Specifically, there were significantly fewer circulating CD56-bright NK cells in patients with FMS, although both the major circulating NK cell subsets, CD56-bright and CD56-dim, were depleted in FMS.
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We next investigated whether a decrease in circulating NK cells was a result of an overall reduction of NK cells in patients with FMS or tissue redistribution. As NK cells can get recruited to damaged peripheral nerves and a considerable number of patients with FMS show [small-fiber neuropathy], we hypothesized that a decrease in circulating NK cells [...] may be associated with their recruitment to and consequent degeneration of peripheral nerves in patients with FMS.
Using skin biopsies of FMS cases and matching controls from a cohort collected at the University of Wuerzburg, we found increased expression of the NK activation ligand, ULBP, in the dermal nerve fibers of patients with FMS. Moreover, recruitment of NK cells near dermal nerve fibers was seen predominantly in the skin biopsies of patients with FMS, but not in controls.
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Infected, [cancerous], or stressed cells overexpress ULBPs.
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There was significantly more ULBP [expression] in patients with FMS (P-value=0.003). [...] Recruitment of NK cells [...] correlated with neuronal ULBP expression (P-value = 0.01). Furthermore, both ULBP expression and NK cells recruitment were correlated with the FSQ scores (P-value=0.01; P value=0.04, respectively).
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There is only a weak [correlation] between ULBP expression and [small fiber neuropathy] (P value=0.07).
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It is possible that in some patients with FMS, even when the nerves are being marked by ULBP for removal by NK cells, they continue to regrow, masking [small fiber neuropathy] but not preventing pain symptoms.
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It is unclear if ULBP expression on the peripheral nerves is a cause, consequence, or exacerbator of the nerve damage in FMS. In addition, we do not know if ULBP is the only NK activation ligand expressed by the peripheral nerves in FMS.
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There is evidence that viral infections can trigger FMS and chronic fatigue syndrome. Thus, a chronic or latent viral infection of sensory neurons may lead to the expression of ULBP on the peripheral nerves of patients with FMS.
