Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia (Verma et al., 2021)

Pyrrhus

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Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia (Verma et al., 2021)
https://doi.org/10.1097/j.pain.0000000000002498

Main points:
  1. The authors investigated the Natural Killer (NK) cells of fibromyalgia patients.
  2. The authors found low numbers of NK cells in the blood.
  3. The authors found somewhat unclear evidence for how cytotoxic these NK cells were.
  4. The authors looked at peripheral nerve fibers just under the skin of patients.
  5. The authors found evidence that the nerve fibers were actively attracting NK cells.

This study raises the intriguing question:
  • What is going on inside these peripheral nerves that causes them to call for help from NK cells?

Abstract:
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.
(spacing added for readability)
 

Pyrrhus

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Related publications on fibromyalgia research:

Identification of a MicroRNA Signature for the Diagnosis of Fibromyalgia (Cerda et al., 2015)
https://forums.phoenixrising.me/thr...ture-for-the-diagnosis-of-fibromyalgia.36480/

Fibromyalgia Is Correlated with Retinal Nerve Fiber Layer Thinning (Garcia-Martin et al. 2016)
https://forums.phoenixrising.me/thr...-of-fibromyalgia-patients.61667/#post-2321474

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation (Albrecht et al. 2019)
https://forums.phoenixrising.me/thr...-of-fibromyalgia-patients.61667/#post-2321470

Characterization of dermal skin innervation in fibromyalgia syndrome (Evdomikov et al., 2020)
https://forums.phoenixrising.me/thr...ervation-in-fibromyalgia-syndrome-2020.79404/

Passive transfer of fibromyalgia symptoms from patients to mice (Goebel et al., 2021)
https://forums.phoenixrising.me/thr...antibodies-produce-fm-symptoms-in-mice.84639/

Pain-related post-exertional malaise in ME/CFS and Fibromyalgia: A systematic review and three-level meta-analysis (Barhorst et al., 2021)
https://forums.phoenixrising.me/thr...evel-meta-analysis-barhorst-et-al-2021.85991/
 

Pyrrhus

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The authors found somewhat unclear evidence for how cytotoxic these NK cells were.
Specifically, the investigators performed two separate assays to assess NK cytotoxicity:
Verma et al 2021 said:
NK cell activation after culture with HLA-/- cells revealed a significant increase in CCL4+ and CD107a+ in NK cells from patients with FMS compared with controls.
[...]
Antibody-dependent NK activation (ADNKA) assay measures NK cell activation after incubation with antibody-bound target cells. [...] The ADNKA assay did not show statistically significant differences between cases and controls.

This study raises the intriguing question:
  • What is going on inside these peripheral nerves that causes them to call for help from NK cells?
More specifically, the peripheral nerves expressed "unique long 16–binding protein" (ULBP), which attracts and binds NK cells. According to one paper:
Liu et al 2017 said:
Unique long 16 binding proteins (ULBPs) [...] are a family of ligands for natural-killer group 2D (NKG2D) receptors in humans that are frequently expressed by tumor cells and mediate biological functions of NK cells (12). The majority of studies of NKG2D ligands have traditionally demonstrated their expression only on infected or [cancerous] cells (13,14); whereas other studies have demonstrated that several normal cells and tissues also express NKG2D ligands (15,16).
(emphasis added)
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377380/
 

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Here are some interesting quotes from this paper:

Both central and peripheral nervous systems have been shown to be affected in fibromyalgia (FMS).
[...]
[Genetic] sequencing and proteome-wide studies have identified molecular signatures consistent with low-grade chronic inflammation in patients with FMS.
[...]
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.
[...]
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.
[...]
The Fibromyalgia Survey Questionnaire (FSQ) that assesses the key symptoms of FMS was also administrated, and FSQ severity score was calculated.
[...]
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.
[...]
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.
[...]
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.
[...]
Infected, [cancerous], or stressed cells overexpress ULBPs.
[...]
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).
[...]
There is only a weak [correlation] between ULBP expression and [small fiber neuropathy] (P value=0.07).
[...]
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.
[...]
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.
[...]
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.
 

Pyrrhus

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The paper quotes this other paper, which may help explain the findings:

Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury (Davies et al., 2019)
https://doi.org/10.1016/j.cell.2018.12.022

Abstract:
Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved.

We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons.

Infiltration of cytotoxic NK cells into the sciatic nerve [from the blood] occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity.

This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.
(spacing added for readability)