Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia

Verma, Vivek; Drury, Gillian; Parisien, Marc; Acarlı, Ayşe Nur Özdağ; Al‐Aubodah, Tho‐Alfakar; Nijnik, Anastasia; Wen, Xia; Tugarinov, Nicol; Verner, Maria; Klares, Richie; Linton, Alexander; Krock, Emerson; Urbina, Carlos E. Morado; Winsvold, Bendik S.; Fritsche, Lars G.; Fors, Egil Andreas; Piccirillo, Ciriaco A.; Khoutorsky, Arkady; Svensson, Camilla I.; Fitzcharles, Mary Ann; Ingelmo, Pablo; Bernard, Nicole F.; Dupuy, Franck P.; Üçeyler, Nurcan; Sommer, Claudia; King, Irah L.; Meloto, Carolina B.; Diatchenko, Luda

doi:10.1097/j.pain.0000000000002498

Cited by 19 publications

(23 citation statements)

References 96 publications

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“…Our analysis used markers for cytokine production, chemokine receptor expression, and cell surface markers that allowed us to distinguish all major blood cell types and many of their subtypes. 84 In this hypothesis-free comparison, we found that fibromyalgia patients have fewer circulating NK cells and increased numbers of circulating B cells. As the changes in the NK cells were stronger, we concentrated our study on NK cells.…”

Section: Unbiased Immune Profiling Of Pain Phenotypesmentioning

confidence: 64%

“…The final example presented in this review is based on the results of unbiased immune profiling of peripheral blood mononuclear cells (PBMCs) of fibromyalgia patients compared to healthy controls. 84 Although there is solid evidence regarding the contribution of the immune system to fibromyalgia development, existing studies have typically focused on a specific immune cell subset. 4 , 11 This is true for other chronic pain conditions as well, with the largest focus overall on macrophages/monocytes, T cells, and mast cells.…”

Section: Unbiased Immune Profiling Of Pain Phenotypesmentioning

confidence: 99%

“… The contribution of natural killer cells to the pathogenesis of fibromyalgia based on the results of unbiased immune profiling of fibromyalgia cases and controls (based on Verma et al). 84 Panels show intraepidermal innervation (purple) in control human subjects (left) and patients with fibromyalgia (right). In those with fibromyalgia, but not in the control subjects, intraepidermal nerves express a ligand for NK cell activation, which in turn coaxes NK cells to extravasate from the bloodstream and follow the ligand's gradient.…”

Section: Unbiased Immune Profiling Of Pain Phenotypesmentioning

confidence: 99%

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Omics approaches to discover pathophysiological pathways contributing to human pain

Diatchenko

Parisien

Esfahani

et al. 2022

Pain

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Section: Unbiased Immune Profiling Of Pain Phenotypesmentioning

confidence: 64%

Section: Unbiased Immune Profiling Of Pain Phenotypesmentioning

confidence: 99%

Section: Unbiased Immune Profiling Of Pain Phenotypesmentioning

confidence: 99%

See 1 more Smart Citation

Omics approaches to discover pathophysiological pathways contributing to human pain

Diatchenko

Parisien

Esfahani

et al. 2022

Pain

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“…FM IgG also binds antigens expressed in mouse and human DRGs, further suggesting causal roles of the peripheral nervous system and immune system in FM. Peripheral immune cells, such as NK cells (37) and mast cells (38), have also been linked to FM. Our current study found anti-SGC IgG levels are elevated in individuals with more severe pain, increased pressure pain sensitivity and higher FIQ scores, but are unrelated to CPM.…”

Section: Discussionmentioning

confidence: 99%

Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms

Krock

Urbina

Menezes

et al. 2022

Preprint

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Objective: Transferring fibromyalgia patient IgG to mice induces pain-like behaviour and fibromyalgia IgG binds mouse and human satellite glia cells (SGCs). These findings suggest that autoantibodies could be part of fibromyalgia pathology. However, it is unknown how frequently fibromyalgia patients have anti-SGC antibodies and how anti-SGC antibodies associate with disease severity. Methods: We quantified serum or plasma anti-SGC IgG levels in two fibromyalgia cohorts from Sweden and Canada using an indirect immunofluorescence murine cell culture assay. Fibromyalgia serum IgG binding to human SGCs in human dorsal root ganglia tissue sections was assessed by immunofluorescence (n=14/group). Results: In the cell culture assay anti-SGC IgG levels were increased in both fibromyalgia cohorts compared to controls. Elevated anti-SGC IgG was associated with higher levels of self-reported pain in both cohorts, and higher fibromyalgia impact questionnaire scores and increased pressure sensitivity in the Swedish cohort. Anti-SGC IgG levels were not associated with fibromyalgia duration. Swedish FM patients were clustered into FM-severe and FM-mild groups and the FM-severe group had elevated anti-SGC IgG compared to the FM-mild and controls. Anti-SGC IgG levels detected in culture were positively correlated with increased binding to human SGCs. Moreover, the FM-severe group had elevated IgG binding to human SGCs compared to the FM-mild and control groups. Conclusions: A subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia severity. Screening fibromyalgia patients for anti-SGC antibodies could provide a path to personalized treatment options that target autoantibodies and autoantibody production.

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“…Passive transfer experiments and cell culture incubation along with immunoreaction in tissue sections indicated binding of FMS patient-derived IgG at the dorsal root ganglion level, representing a neuro-inflammatory component via the humoral system [8]. Moreover, a switch from circulating to resident hyper-responsive natural killer (NK) cells in FMS may participate in peripheral neurodegeneration [88]. Both NK activation and autoimmunity are linked to BMP signaling, e.g., via an autocrine activation pathway via BMP receptors and BMP ligands in NK cells [80][81][82], which fits our identified target genes BMP1, BMP2, BMP3, BMP7, BMP6, BMPER, BMPR1B, and, most importantly, BMPR2.…”

Section: Discussionmentioning

confidence: 99%

Distinct CholinomiR Blood Cell Signature as a Potential Modulator of the Cholinergic System in Women with Fibromyalgia Syndrome

Erbacher

Vaknine

Moshitzky

et al. 2022

Cells

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Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson’s disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.

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Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia

Abstract: Supplemental Digital Content is Available in the Text.Fibromyalgia is associated with a dysregulated NK cell activation signature and their accumulation at peripheral nerves.

Cited by 19 publications

References 96 publications

Omics approaches to discover pathophysiological pathways contributing to human pain

Omics approaches to discover pathophysiological pathways contributing to human pain

Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms

Distinct CholinomiR Blood Cell Signature as a Potential Modulator of the Cholinergic System in Women with Fibromyalgia Syndrome

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