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  • 1
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    Synovial fluid neutrophils in oligoarticular juvenile idiopathic arthritis have an altered phenotype and impaired effector functions
    Springer Science and Business Media LLC ; 2021
    In:  Arthritis Research & Therapy Vol. 23, No. 1 ( 2021-12)
    Details
    In: Arthritis Research & Therapy, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2021-12)
    Abstract: Neutrophils are the most prevalent immune cells in the synovial fluid in inflamed joints of children with oligoarticular juvenile idiopathic arthritis (JIA). Despite this, little is known about neutrophil function at the site of inflammation in JIA and how local neutrophils contribute to disease pathogenesis. This study aimed to characterize the phenotype and function of synovial fluid neutrophils in oligoarticular JIA. Methods Neutrophils obtained from paired blood and synovial fluid from patients with active oligoarticular JIA were investigated phenotypically ( n  = 17) and functionally (phagocytosis and oxidative burst, n  = 13) by flow cytometry. In a subset of patients ( n  = 6), blood samples were also obtained during inactive disease at a follow-up visit. The presence of CD206-expressing neutrophils was investigated in synovial biopsies from four patients by immunofluorescence. Results Neutrophils in synovial fluid had an activated phenotype, characterized by increased CD66b and CD11b levels, and most neutrophils had a CD16 hi CD62L low aged phenotype. A large proportion of the synovial fluid neutrophils expressed CD206, a mannose receptor not commonly expressed by neutrophils but by monocytes, macrophages, and dendritic cells. CD206-expressing neutrophils were also found in synovial tissue biopsies. The synovial fluid neutrophil phenotype was not dependent on transmigration alone. Functionally, synovial fluid neutrophils had reduced phagocytic capacity and a trend towards impaired oxidative burst compared to blood neutrophils. In addition, the effector functions of the synovial fluid neutrophils correlated negatively with the proportion of CD206 + neutrophils. Conclusions Neutrophils in the inflamed joint in oligoarticular JIA were altered, both regarding phenotype and function. Neutrophils in the synovial fluid were activated, had an aged phenotype, had gained monocyte-like features, and had impaired phagocytic capacity. The impairment in phagocytosis and oxidative burst was associated with the phenotype shift. We speculate that these neutrophil alterations might play a role in the sustained joint inflammation seen in JIA.
    Type of Medium: Online Resource
    ISSN: 1478-6362
    URL: Article
    DOI: 10.1186/s13075-021-02483-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041668-4
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  • 2
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    Synovial fibroblasts from children with oligoarticular juvenile idiopathic arthritis induce migration and prolong viability of neutrophils
    Frontiers Media SA ; 2024
    In:  Frontiers in Pediatrics Vol. 12 ( 2024-7-3)
    Details
    In: Frontiers in Pediatrics, Frontiers Media SA, Vol. 12 ( 2024-7-3)
    Abstract: Little is known of the processes that trigger neutrophil activation in the joint of patients with oligoarticular juvenile idiopathic arthritis (oJIA), and if synovial fibroblasts (S-Fib) play an important role in the activation. Therefore, we aimed to investigate whether S-Fib derived from oJIA patients drive neutrophil activation. Methods Synovial fluid (SF) was collected from patients with oJIA. S-Fib were isolated from the SF of n = 7 patients through passaging. Subsequently, the S-Fib were primed or not with 20% of pooled SF. Supernatants were used to study migration of neutrophils in a transwell system. Additionally, the influence of S-Fib on neutrophils were studied in co-cultures. Phenotype and viability were assessed by flow cytometry. Neutrophil function was tested through the production of reactive oxygen species (ROS), and supernatants were tested for myeloperoxidase (MPO) release and elastase activity. Results Supernatants of S-Fib induced neutrophil migration ( n = 5, p = 0.0491), which was further pronounced using supernatants from SF-primed S-Fib ( p = 0.0063). Additionally, co-culture between SF-primed S-Fib and neutrophils resulted in prolonged viability ( n = 5, p = 0.0094), with little effect on activation markers, e.g., CD11b. Conversely, co-culture did not induce functional alterations ( n = 4), such as production of ROS ( p & gt; 0.1570), release of MPO ( p & gt; 0.4934) or elastase activity ( p & gt; 0.0904). Finally, supernatant stimulation did not replicate the results of prolonged viability ( p = 0.9102), suggesting a role of cell-contact. Conclusion S-Fib from patients with oJIA induce migration of neutrophils via soluble mediators and, in addition, S-Fib prolong neutrophil viability in a cell-contact dependent manner. These mechanisms could be important for accumulation of neutrophils during arthritis.
    Type of Medium: Online Resource
    ISSN: 2296-2360
    URL: Article
    DOI: 10.3389/fped.2024.1376371
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
    detail.hit.zdb_id: 2711999-3
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  • 3
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    Table_1.docx
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 14 ( 2023-5-22)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-5-22)
    Abstract: Monocytes are key effector cells in inflammatory processes. We and others have previously shown that synovial monocytes in childhood-onset arthritis are activated. However, very little is known about how they contribute to disease and attain their pathological features. Therefore, we set out to investigate the functional alterations of synovial monocytes in childhood-onset arthritis, how they acquire this phenotype, and whether these mechanisms could be used to tailorize treatment. Methods The function of synovial monocytes was analysed by assays believed to reflect key pathological events, such as T-cell activation-, efferocytosis- and cytokine production assays using flow cytometry in untreated oligoarticular juvenile idiopathic arthritis (oJIA) patients (n=33). The effect of synovial fluid on healthy monocytes was investigated through mass spectrometry and functional assays. To characterize pathways induced by synovial fluid, we utilized broad-spectrum phosphorylation assays and flow cytometry, as well as inhibitors to block specific pathways. Additional effects on monocytes were studied through co-cultures with fibroblast-like synoviocytes or migration in transwell systems. Results Synovial monocytes display functional alterations with inflammatory and regulatory features, e.g., increased ability to induce T-cell activation, resistance to cytokine production following activation with LPS and increased efferocytosis. In vitro , synovial fluid from patients induced the regulatory features in healthy monocytes, such as resistance to cytokine production and increased efferocytosis. IL-6/JAK/STAT signalling was identified as the main pathway induced by synovial fluid, which also was responsible for a majority of the induced features. The magnitude of synovial IL-6 driven activation in monocytes was reflected in circulating cytokine levels, reflecting two groups of low vs. high local and systemic inflammation. Remaining features, such as an increased ability to induce T-cell activation and markers of antigen presentation, could be induced by cell-cell interactions, specifically via co-culture with fibroblast-like synoviocytes. Conclusions Synovial monocytes in childhood-onset arthritis are functionally affected and contribute to chronic inflammation, e.g., via promoting adaptive immune responses. These data support a role of monocytes in the pathogenesis of oJIA and highlight a group of patients more likely to benefit from targeting the IL-6/JAK/STAT axis to restore synovial homeostasis.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2023.1190018
    DOI: 10.3389/fimmu.2023.1190018.s001
    DOI: 10.3389/fimmu.2023.1190018.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 4
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    Table5.xlsx
    Frontiers Media SA ; 2023
    In:  Frontiers in Pediatrics Vol. 10 ( 2023-1-9)
    Details
    In: Frontiers in Pediatrics, Frontiers Media SA, Vol. 10 ( 2023-1-9)
    Abstract: Many children with juvenile idiopathic arthritis (JIA) have autoantibodies, targeting nuclear components (anti-nuclear antibodies, ANA). ANA in JIA is associated with uveitis, an eye inflammation which may cause permanent vision impairment if not detected and treated. However, ANA-testing is neither specific nor sensitive enough to be a clinically reliable predictor of uveitis risk, and the precise autoantigens targeted by ANA in JIA are largely unknown. If identified, specific autoantibodies highly associated with uveitis could be used as biomarkers to facilitate identification of JIA patients at risk. Methods Antibodies from six ANA-positive, oligoarticular JIA patients, with and without uveitis, were explored by two large-scale methods: (1) screening against 42,100 peptides on an autoimmunity profiling planar array, and (2) immunoprecipitations from cell lysates with antigen identification by mass spectrometry. Three hundred thirty-five peptide antigens, selected from proteins identified in the large-scale methods and the scientific literature were investigated using a bead-based array in a cohort of 56 patients with oligoarticular- or RF-negative polyarticular JIA, eight of which were having current or previous uveitis. Results In the planar array, reactivity was detected against 332 peptide antigens. The immunoprecipitations identified reactivity towards 131 proteins. Only two proteins were identified by both methods. In the bead-based array of selected peptide antigens, patients with uveitis had a generally higher autoreactivity, seen as higher median fluorescence intensity (MFI) across all antigens, compared to patients without uveitis. Reactivity towards 17 specific antigens was significantly higher in patients with uveitis compared to patients without uveitis. Hierarchical clustering revealed that patients with uveitis clustered together. Conclusion This study investigated autoantigens in JIA and uveitis, by combining two exploratory methods and confirmation in a targeted array. JIA patients with current or a history of uveitis had significantly higher reactivity towards 17 autoantigens and a generally higher autoreactivity compared to JIA patients without uveitis. Hierarchical clustering suggests that a combination of certain autoantibodies, rather than reactivity towards one specific antigen, is associated with uveitis. Our analysis of autoantibodies associated with uveitis in JIA could be a starting point for identification of prognostic biomarkers useful in JIA clinical care.
    Type of Medium: Online Resource
    ISSN: 2296-2360
    URL: Article
    URL: Article
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    URL: Article
    DOI: 10.3389/fped.2022.1091308
    DOI: 10.3389/fped.2022.1091308.s001
    DOI: 10.3389/fped.2022.1091308.s002
    DOI: 10.3389/fped.2022.1091308.s003
    DOI: 10.3389/fped.2022.1091308.s004
    DOI: 10.3389/fped.2022.1091308.s005
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2711999-3
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  • 5
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    Mismatch between circulating cytokines and spontaneous cytokine production by leukocytes in hyperinflammatory COVID-19
    Oxford University Press (OUP) ; 2021
    In:  Journal of Leukocyte Biology Vol. 109, No. 1 ( 2021-01-01), p. 115-120
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 109, No. 1 ( 2021-01-01), p. 115-120
    Abstract: The disease COVID-19 has developed into a worldwide pandemic. Hyperinflammation and high levels of several cytokines, for example, IL-6, are observed in severe COVID-19 cases. However, little is known about the cellular origin of these cytokines. Here, we investigated whether circulating leukocytes from patients with COVID-19 had spontaneous cytokine production. Patients with hyperinflammatory COVID-19 (n = 6) and sepsis (n = 3) were included at Skåne University Hospital, Sweden. Healthy controls were also recruited (n = 5). Cytokines were measured in COVID-19 and sepsis patients using an Immulite immunoassay system. PBMCs were cultured with brefeldin A to allow cytokine accumulation. In parallel, LPS was used as an activator. Cells were analyzed for cytokines and surface markers by flow cytometry. High levels of IL-6 and measurable levels of IL-8 and TNF, but not IL-1β, were observed in COVID-19 patients. Monocytes from COVID-19 patients had spontaneous production of IL-1β and IL-8 (P = 0.0043), but not of TNF and IL-6, compared to controls. No spontaneous cytokine production was seen in lymphocytes from either patients or controls. Activation with LPS resulted in massive cytokine production by monocytes from COVID-19 patients and healthy controls, but not from sepsis patients. Finally, monocytes from COVID-19 patients produced more IL-1β than from healthy controls (P = 0.0087) when activated. In conclusion, monocytes contribute partly to the ongoing hyperinflammation by production of IL-1β and IL-8. Additionally, they are responsive to further activation. This data supports the notion of IL-1β blockade in treatment of COVID-19. However, the source of the high levels of IL-6 remains to be determined.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    URL: Article
    DOI: 10.1002/JLB.5COVBCR0720-310RR
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 6
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    Children with oligoarticular juvenile idiopathic arthritis have skewed synovial monocyte polarization pattern with functional impairment—a distinct inflammatory pattern for oligoarticular juvenile arthritis
    Springer Science and Business Media LLC ; 2020
    In:  Arthritis Research & Therapy Vol. 22, No. 1 ( 2020-12)
    Details
    In: Arthritis Research & Therapy, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2020-12)
    Abstract: Juvenile idiopathic arthritis (JIA) is an umbrella term of inflammatory joint diseases in children. Oligoarthritis is the most common form in the Western world, representing roughly 60% of all patients. Monocytes and macrophages play an important role in adult arthritides, but their role in oligoarticular JIA is less studied. Polarization highly influences monocytes’ and macrophages’ effector functions, broadly separated into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. Here, we set out to investigate the polarization pattern and functional aspects of synovial monocytes in oligoarticular juvenile idiopathic arthritis (JIA). Methods Paired synovial fluid, blood samples ( n  = 13), and synovial biopsies ( n  = 3) were collected from patients with untreated oligoarticular JIA. Monocytes were analyzed for polarization markers by flow cytometry and qPCR. Effector function was analyzed by a phagocytosis assay. Polarization of healthy monocytes was investigated by stimulation with synovial fluid in vitro. Monocyte/macrophage distribution, polarization, and mRNA expression were investigated in biopsies by immunohistochemistry, immunofluorescence, and in situ hybridization. Results Children with oligoarticular JIA have polarized synovial fluid monocytes of a specific M1(IFNγ)/M2(IL-4)-like pattern. This was evidenced by increased surface expression of CD40 ( p   〈  0.001), CD86 ( p   〈  0.001), and CD206 ( p   〈  0.001), but not CD163, as compared to paired circulating monocytes. Additionally, polarization was extensively explored at the mRNA level and synovial fluid monocytes differentially expressed classical markers of M1(IFNγ)/M2(IL-4) polarization compared to circulating monocytes. Synovial fluid monocytes were functionally affected, as assessed by reduced capacity to phagocytose ( p   〈  0.01). Synovial fluid induced M2 markers (CD16 and CD206), but not M1 (CD40) or CD86 in healthy monocytes and did not induce cytokine production. Single and co-expression of surface CD40 and CD206, as well as mRNA expression of IL-10 and TNF, was observed in monocytes/macrophages in synovial biopsies. Conclusion Children with untreated oligoarticular JIA have similar and distinct synovial fluid monocyte polarization pattern of mixed pro- and anti-inflammatory features. This pattern was not exclusively a result of the synovial fluid milieu as monocytes/macrophages in the synovial membrane show similar patterns. Our study highlights a distinct polarization pattern in oligoarticular JIA, which could be utilized for future treatment strategies.
    Type of Medium: Online Resource
    ISSN: 1478-6362
    URL: Article
    DOI: 10.1186/s13075-020-02279-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 7
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    Can misfolded proteins be beneficial? The HAMLET case
    Informa UK Limited ; 2009
    In:  Annals of Medicine Vol. 41, No. 3 ( 2009-01), p. 162-176
    Details
    In: Annals of Medicine, Informa UK Limited, Vol. 41, No. 3 ( 2009-01), p. 162-176
    Type of Medium: Online Resource
    ISSN: 0785-3890 , 1365-2060
    URL: Article
    DOI: 10.1080/07853890802502614
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2009
    detail.hit.zdb_id: 2028104-3
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  • 8
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    Eight Nucleotide Substitutions Inhibit Splicing to HPV-16 3′-Splice Site SA3358 and Reduce the Efficiency by which HPV-16 Increases the Life Span of Primary Human Keratinocytes
    Public Library of Science (PLoS) ; 2013
    In:  PLoS ONE Vol. 8, No. 9 ( 2013-9-9), p. e72776-
    Details
    In: PLoS ONE, Public Library of Science (PLoS), Vol. 8, No. 9 ( 2013-9-9), p. e72776-
    Type of Medium: Online Resource
    ISSN: 1932-6203
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    DOI: 10.1371/journal.pone.0072776
    DOI: 10.1371/journal.pone.0072776.g001
    DOI: 10.1371/journal.pone.0072776.g002
    DOI: 10.1371/journal.pone.0072776.g003
    DOI: 10.1371/journal.pone.0072776.g004
    DOI: 10.1371/journal.pone.0072776.g005
    DOI: 10.1371/journal.pone.0072776.g006
    DOI: 10.1371/journal.pone.0072776.g007
    DOI: 10.1371/journal.pone.0072776.g008
    DOI: 10.1371/journal.pone.0072776.t001
    DOI: 10.1371/journal.pone.0072776.t002
    DOI: 10.1371/journal.pone.0072776.s001
    DOI: 10.1371/journal.pone.0072776.s002
    DOI: 10.1371/journal.pone.0072776.s003
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2013
    detail.hit.zdb_id: 2267670-3
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  • 9
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    Table_2.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 12 ( 2022-1-13)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2022-1-13)
    Abstract: Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4 + T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in an in vitro transmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4 + T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.795260
    DOI: 10.3389/fimmu.2021.795260.s001
    DOI: 10.3389/fimmu.2021.795260.s002
    DOI: 10.3389/fimmu.2021.795260.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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