| 11. |
- Fanton, Silvia, et al.
(författare)
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Anti-satellite glia cell IgG antibodies in fibromyalgia patients are related to symptom severity and to metabolite concentrations in thalamus and rostral anterior cingulate cortex.
- 2023
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Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 114, s. 371-382
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Tidskriftsartikel (refereegranskat)abstract
- Recent translational work has shown that fibromyalgia might be an autoimmune condition with pathogenic mechanisms mediated by a peripheral, pain-inducing action of immunoglobulin G (IgG) antibodies binding to satellite glia cells (SGC) in the dorsal root ganglia. A first clinical assessment of the postulated autoimmunity showed that fibromyalgia subjects (FMS) had elevated levels of antibodies against SGC (termed anti-SGC IgG) compared to healthy controls and that anti-SGC IgG were associated with a more severe disease status. The overarching aim of the current study was to determine whether the role of anti-SGC IgG in driving pain is exclusively through peripheral mechanisms, as indirectly shown so far, or could be attributed also to central mechanisms. To this end, we wanted to first confirm, in a larger cohort of FMS, the relation between anti-SGC IgG and pain-related clinical measures. Secondly, we explored the associations of these autoantibodies with brain metabolite concentrations (assessed via magnetic resonance spectroscopy, MRS) and pressure-evoked cerebral pain processing (assessed via functional magnetic resonance imaging, fMRI) in FMS. Proton MRS was performed in the thalamus and rostral anterior cingulate cortex (rACC) of FMS and concentrations of a wide spectrum of metabolites were assessed. During fMRI, FMS received individually calibrated painful pressure stimuli corresponding to low and high pain intensities. Our results confirmed a positive correlation between anti-SGC IgG and clinical measures assessing condition severity. Additionally, FMS with high anti-SGC IgG levels had higher pain intensity and a worse disease status than FMS with low anti-SGC IgG levels. Further, anti-SGC IgG levels negatively correlated with metabolites such as scyllo-inositol in thalamus and rACC as well as with total choline and macromolecule 12 in thalamus, thus linking anti-SGC IgG levels to the concentration of metabolites in the brain of FMS. However, anti-SGC IgG levels in FMS were not associated with the sensitivity to pressure pain or the cerebral processing of evoked pressure pain. Taken together, our results suggest that anti-SGC IgG might be clinically relevant for spontaneous, non-evoked pain. Our current and previous translational and clinical findings could provide a rationale to try new antibody-related treatments in FMS.
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| 12. |
- Goebel, Andreas, et al.
(författare)
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Passive transfer of fibromyalgia symptoms from patients to mice
- 2021
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 131:13
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.
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| 13. |
- He, Yibo, et al.
(författare)
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A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis.
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certainRA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
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| 14. |
- Khoury, Spiro, et al.
(författare)
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Identification of Lipid Biomarkers for Chronic Joint Pain Associated with Different Joint Diseases
- 2023
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Lipids, especially lysophosphatidylcholine LPC16:0, have been shown to be involved in chronic joint pain through the activation of acid-sensing ion channels (ASIC3). The aim of the present study was to investigate the lipid contents of the synovial fluids from controls and patients suffering from chronic joint pain in order to identify characteristic lipid signatures associated with specific joint diseases. For this purpose, lipids were extracted from the synovial fluids and analyzed by mass spectrometry. Lipidomic analyses identified certain choline-containing lipid classes and molecular species as biomarkers of chronic joint pain, regardless of the pathology, with significantly higher levels detected in the patient samples. Moreover, correlations were observed between certain lipid levels and the type of joint pathologies. Interestingly, LPC16:0 levels appeared to correlate with the metabolic status of patients while other choline-containing lipids were more specifically associated with the inflammatory state. Overall, these data point at selective lipid species in synovial fluid as being strong predictors of specific joint pathologies which could help in the selection of the most adapted treatment.
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| 15. |
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| 16. |
- Krock, Emerson, et al.
(författare)
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Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms
- 2023
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 164:8, s. 1828-1840
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Tidskriftsartikel (refereegranskat)abstract
- Transferring fibromyalgia patient immunoglobulin G (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. Here, we quantified serum or plasma anti-SGC IgG levels in 2 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 also assessed by immunofluorescence. In the cell culture assay, anti-SGC IgG levels were increased in both fibromyalgia cohorts compared with control group. 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 fibromyalgia (FM) patients were clustered into FM-severe and FM-mild groups, and the FM-severe group had elevated anti-SGC IgG compared with the FM-mild group and control group. Anti-SGC IgG levels detected in culture positively correlated with increased binding to human SGCs. Moreover, the FM-severe group had elevated IgG binding to human SGCs compared with the FM-mild and control groups. These results demonstrate that a subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia symptoms. 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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| 17. |
- Lampa, Jon, et al.
(författare)
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Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:31, s. 12728-33
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Tidskriftsartikel (refereegranskat)abstract
- During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
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| 18. |
- Lund, Harald, et al.
(författare)
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CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier
- 2024
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 221:2
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Tidskriftsartikel (refereegranskat)abstract
- In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163(+) macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.
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| 19. |
- Moller, Kristina Angeby, et al.
(författare)
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Using gait analysis to assess weight bearing in rats with Freund's complete adjuvant-induced monoarthritis to improve predictivity : Interfering with the cyclooxygenase and nerve growth factor pathways
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 756, s. 75-84
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Tidskriftsartikel (refereegranskat)abstract
- Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund's complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors >= anti-NGF antibody > COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain. (C) 2015 Elsevier B.V. All rights reserved.
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| 20. |
- Palada, Vinko, et al.
(författare)
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Characterization of neuroinflammation and periphery-to-CNS inflammatory cross-talk in patients with disc herniation and degenerative disc disease.
- 2019
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 75, s. 60-71
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to identify inflammatory cytokines/chemokines associated with neuroinflammation and periphery-to-CNS inflammatory cross-talk in degenerative disc disease (DDD) and lumbar disc herniation (LDH), common causes of low back pain (LBP). A secondary aim was to investigate the associations between cytokines and symptom severity.METHODS: In total, 40 DDD and 40 LDH patients were recruited from a surgical waiting list, as well as 39 healthy controls (HC) and 40 cerebrospinal fluid (CSF) controls. The subjects completed questionnaires and pressure algometry was performed at the lumbar spine and forearm. The CSF, serum and disc tissues were collected during surgery. Inflammatory mediators TNF, INFg, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and MCP1 were analysed by immunoassay (Meso Scale Discovery) and quantitative real-time polymerase chain reaction (qPCR) was used for analysis of IL-6, IL-8, MCP1 and TSPO expression in intervertebral discs (IVDs).RESULTS: In the LDH group, we found elevated IL-8 concentrations in CSF indicating neuroinflammation, while IL-8 and MCP1 concentrations in serum were lower compared to HC. The IVD expression of IL-6, IL-8 and TSPO was lower in LDH patients compared to DDD. LDH patients had a positive correlation between IL-8 concentrations in CSF and serum and IL-8 in CSF was associated with higher pain intensity and increased spinal pressure pain sensitivity. The MCP1 concentration in serum was associated with higher global pain ratings and increased spinal pressure pain sensitivity, while IL-6 serum concentration correlated with the intensity of the neuropathic pain component (leg pain) in LDH patients. IVD expression of TSPO in LDH patients was associated with increased intensity of back pain. No differences were found in cytokine CSF concentrations between DDD patients and CSF controls, but DDD patients had lower IL-8 and MCP1 serum concentrations than HC. In female DDD patients, IL-8 and MCP1 concentrations in serum were associated with increased intensity of back pain.CONCLUSION: Our results suggest that neuroinflammation mediated by elevated IL-8 concentrations in CSF and IL-8 mediated periphery-to-CNS inflammatory cross-talk contributes to pain in LDH patients and suggest a link between TSPO expression in discs and low back pain.
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