| 1. |
- Andersson, Karin, 1972, et al.
(författare)
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Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.
- 2018
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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. - 1091-6490. ; 115:51
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
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| 2. |
- Chandrasekaran, Venkatagaran, et al.
(författare)
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Cohesin-Mediated Chromatin Interactions and Autoimmunity
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFN gamma signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.
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| 3. |
- Erlandsson, Malin, 1972, et al.
(författare)
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IGF1R signalling is a guardian of self-tolerance restricting autoantibody production.
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14+ APCs, we investigated the role that IGF1R plays during adaptive immune responses.The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14+ cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing.Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S256-phosphorylated FoxO1+ APCs, and an increased frequency of IgM+CD21+ B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII+CD11b+ APCs ensured favourable conditions for their communication with IgM+ B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14+ APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14+ APCs.In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.
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| 4. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis
- 2019
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Ingår i: BMC Med. - : Springer Science and Business Media LLC. - 1741-7015. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesSince low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study.MethodsA CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52years) and in 132 female patients after ischemic stroke (mean age 56years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1(high) and IGF1(low) groups. A 5-year prospective follow-up for new CVD events was completed in all RA patients. The Mantel-Cox analysis and event-free survival curves were prepared. Unsupervised clustering of proteins within the IGF1 signaling pathway was employed to identify their association with eCVR.ResultsLow IGF1 resulted in a higher eCVR in RA patients (7.2% and 3.3%, p=0.0063) and in stroke (9.3% and 7.1%, p=0.033). RA had higher rate for new CVD events at prospective follow-up (OR 4.96, p=0.028). Hypertension was the major risk factor associated with low IGF1 in RA and stroke. In hypertension, IGF1 was no longer responsible for intracellular activation and lost its correlation to IRS1/2 adaptor proteins. The clustering analysis confirmed that combination of low IGF1 and IRS1/2 with high IL6, insulin, and glucose predisposed to high eCVR and emphasized the functional role of serum IGF1.ConclusionsLow serum IGF1 precedes and predicts development of early CVD events in female RA patients. Hypertension and aberrant IGF1 receptor signaling are highlighted as the important contributors to IGF1-related CVD events.
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| 5. |
- Ferrannini, E., et al.
(författare)
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Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man
- 2020
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 102
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Tidskriftsartikel (refereegranskat)abstract
- Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications. © 2019 Elsevier Inc.
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| 6. |
- Giglio, Daniel, 1977, et al.
(författare)
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Downregulation of toll-like receptor 4 and IL-6 following irradiation of the rat urinary bladder
- 2016
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Ingår i: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 43:7, s. 698-705
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology behind radiation cystitis is poorly understood. Here we investigated whether bladder irradiation affects the immune system of the rat urinary bladder. Female rats were sedated and exposed to one single radiation dose of 20Gy or only sedated (controls) and killed 16h to 14days later. Rats were placed in a metabolic cage at 16h, 3days, 7days and 14days following bladder irradiation. The urinary bladders were harvested and analysed with qPCR, immunohistochemistry and/or Western blot for the expression of interferon (IFN)-, interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, nitric oxide synthases (eNOS, iNOS and nNOS), tumour necrosis factor (TNF)- and toll-like receptor 4 (TLR4). Urine was collected and analysed for IL-6 and nitrite (reflecting nitric oxide activity) with ELISA and the Griess reaction, respectively. Irradiation increased bladder frequency and decreased voiding volumes 14days following bladder irradiation. Bladder irradiation increased the expression of IL-10 and collagen in the bladder, while TLR4 and IL-6 expressions were decreased in the urothelium concomitantly with a decrease in mast cells in the submucosa and urine levels of IL-6 and nitrite. The present findings show that bladder irradiation leads to urodynamic changes in the bladder and may suppress important immunoregulatory pathways in the urinary bladder.
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| 7. |
- Gravina, Giacomo, et al.
(författare)
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Survivin in autoimmune diseases.
- 2017
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Ingår i: Autoimmunity reviews. - : Elsevier BV. - 1873-0183 .- 1568-9972. ; 16:8, s. 845-855
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Forskningsöversikt (refereegranskat)abstract
- Survivin is a protein functionally important for cell division, apoptosis, and possibly, for micro-RNA biogenesis. It is an established marker of malignant cell transformation. In non-malignant conditions, the unique properties of survivin make it indispensable for homeostasis of the immune system. Indeed, it is required for the innate and adaptive immune responses, controlling differentiation and maintenance of CD4(+) and CD8(+) memory T-cells, and in B cell maturation. Recently, survivin has emerged as an important player in the pathogenesis of autoimmune diseases. Under the conditions of unreserved inflammation, survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies. In this context, survivin takes its place as a diagnostic and prognostic marker in rheumatoid arthritis, psoriasis, systemic sclerosis and pulmonary arterial hypertension, neuropathology and multiple sclerosis, inflammatory bowel diseases and oral lichen planus. In this review, we summarise the knowledge about non-malignant properties of survivin and focus on its engagement in cellular and molecular pathology of autoimmune diseases. The review highlights utility of survivin measures for clinical applications. It provides rational for the survivin inhibiting strategies and presents results of recent reports on survivin inhibition in modern therapies of cancers and autoimmune diseases.
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| 8. |
- Sun, Jie, 1977, et al.
(författare)
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Insights into the Mechanism for Vertical Graphene Growth by Plasma-Enhanced Chemical Vapor Deposition
- 2022
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Ingår i: Acs Applied Materials & Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 14:5, s. 7152-7160
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Tidskriftsartikel (refereegranskat)abstract
- Vertically oriented graphene (VG) has attracted attention for years, but the growth mechanism is still not fully revealed. The electric field may play a role, but the direct evidence and exactly what role it plays remains unclear. Here, we conduct a systematic study and find that in plasma-enhanced chemical vapor deposition, the VG growth preferably occurs at spots where the local field is stronger, for example, at GaN nanowire tips. On almost round-shaped nanoparticles, instead of being perpendicular to the substrate, the VG grows along the field direction, that is, perpendicular to the particles' local surfaces. Even more convincingly, the sheath field is screened to different degrees, and a direct correlation between the field strength and the VG growth is observed. Numerical calculation suggests that during the growth, the field helps accumulate charges on graphene, which eventually changes the cohesive graphene layers into separate three-dimensional VG flakes. Furthermore, the field helps attract charged precursors to places sticking out from the substrate and makes them even sharper and turn into VG. Finally, we demonstrate that the VG-covered nanoparticles are benign to human blood leukocytes and could be considered for drug delivery. Our research may serve as a starting point for further vertical two-dimensional material growth mechanism studies.
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| 9. |
- Svensson, Mattias, 1982, et al.
(författare)
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Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination.
- 2015
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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. - 1091-6490. ; 112:48
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Tidskriftsartikel (refereegranskat)abstract
- Switched antibody classes are important for efficient immune responses. Aberrant antibody production to otherwise harmless antigens may result in autoimmunity. The protein kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before. Herein we describe a previously unappreciated role for Flt3 in IgG1 class-switch recombination (CSR) and production. We show that Flt3 is reexpressed on B-cell lymphoma 6(+) germinal center B cells in vivo and following LPS activation of peripheral B cells in vitro. Absence of Flt3 signaling in Flt3 ligand-deficient mice results in impaired IgG1 CSR and accumulation of IgM-secreting plasma cells. On activated B cells, Flt3 is coexpressed and functions in synergy with the common-gamma chain receptor family. B cells from Flt3 ligand-deficient mice have impaired IL-4R signaling, with reduced phosphorylation of signal transducer and activator of transcription (Stat) 6, and demonstrate a failure to initiate CSR to IgG1 with low expression of γ1 germ-line transcripts, resulting in impaired IgG1 production. Thus, functional synergy between Flt3 and IL-4R signaling is critical for Stat-mediated regulation of sterile γ1 germ-line transcripts and CSR to IgG1.
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| 10. |
- Wasén, Caroline, 1990, et al.
(författare)
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Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models
- 2024
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-β (Aβ) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aβ plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aβ1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aβ clearance and accumulation of amyloid plaques.
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| 11. |
- Wasén, Caroline, et al.
(författare)
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Epidermal growth factor receptor function in the human urothelium
- 2018
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Ingår i: International Urology and Nephrology. - : Springer Science and Business Media LLC. - 0301-1623 .- 1573-2584. ; 50:4, s. 647-656
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Tidskriftsartikel (refereegranskat)abstract
- © 2018, The Author(s). Purpose: Epidermal growth factor receptor (EGFr)-targeted therapy may be used in subgroups of patients with urinary bladder cancer. Here we assessed the role of EGFr in urothelial proliferation and migration in a two- and three-dimensional cell culture system. Methods: UROtsa cells derived from normal urothelium and malignant T24 cells were cultured in a Type I collagengel. Proliferation and migration of urothelial cells, in the absence and presence of the EGFr inhibitor cetuximab, were assessed with a proliferation test (ATCC) and with the Axioplan 2 imaging microscope with a motorized stage (Carl Zeiss), respectively. The expressions of cytokeratin (CK) 17, CK20, EGFr, pEGFr, laminin, occludin and zonula occludens 1 (ZO-1) were assessed with immunohistochemistry and/or western blot. Results: UROtsa spheroids were formed after 7days in culture, while T24 cells did not form spheroids. UROtsa expressed CK20 but not laminin or CK17 and consequently resembled umbrella cells. In UROtsa and T24, cetuximab inhibited urothelial proliferation, induced cleavage of EGFr and/or pEGFR but did not affect urothelial migration. The tight junction protein occludin was cleaved, and the formation of cellular spheroids was inhibited in UROtsa by the presence of cetuximab. Conclusions: EGFr modulates urothelial proliferation and the formation of the three-dimensional structure of the urothelium possibly by interfering with occludin. The present data also show a cell culture technique enabling phenotypically normal urothelial cells to form epithelial structures in contrast to malignant urothelial cells.
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| 12. |
- Wasén, Caroline, et al.
(författare)
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Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8(+)T Cells in Rheumatoid Arthritis
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Objective:Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8(+)T cell memory formation through a microRNA (miR) dependent mechanism. Methods:Phenotypes of CD8(+)T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry. A microarray analysis was used to screen for differences in miR expression. Sorted CD8(+)cells werein vitrostimulated with nicotine and analyzed for transcription of miRs and genes related to memory programming by qPCR. Results:CD27(+)CD107a(-)CD8(+)T cells, defining a naive-memory population, had low expression of PD-1. Additionally, the CD27(+)population was more frequent in smokers (p= 0.0089). Smokers were recognized by differential expression of eight miRs. Let-7c-5p, let-7d-5p and let-7e-5p, miR-92a-3p, miR-150-5p, and miR-181-5p were up regulated, while miR-3196 and miR-4723-5p were down regulated. These miRs were predicted to target proteins within the FOXO-signaling pathway involved in CD8(+)memory programming. Furthermore, miR-92a-3p was differentially expressed in CD8(+)cells with naive-memory predominance. Nicotine exposure of CD8(+)cells induced the expression of miR-150-5p and miR-181a-5p in the naive-memory cellsin vitro. Additionally, nicotine exposure inverted the ratio between mRNAs of proteins in the FOXO pathway and their targeting miRs. Conclusions:Smokers have a high prevalence of CD8(+)T cells with a naive-memory phenotype. These cells express a miR profile that interacts with the memory programming conducted through the FOXO pathway.
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| 13. |
- Wasén, Caroline, et al.
(författare)
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Smoking activates cytotoxic CD8(+) T cells and causes survivin release in rheumatoid arthritis
- 2017
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 78, s. 101-110
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Tidskriftsartikel (refereegranskat)abstract
- CD8(+) T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8(+) T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8(+) T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8(+) T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8(+) T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1(-)IL-7R(+) CD8(+) T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+ T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+ T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA. (C) 2016 The Authors. Published by Elsevier Ltd.
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| 14. |
- Wasén, Caroline
(författare)
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Smoking and T cell co-stimulation in rheumatoid arthritis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis I investigated if smoking limits the co-stimulatory system of CD8+ T cells in rheumatoid arthritis (RA). I took special interest in the co-inhibitory receptor PD-1 and its ligand PD-L1. Blood samples from RA patients with known smoking status and experimental models of RA (RA mice) in which orally administered nicotine simulated smoking were used. Additionally, CD8+ T cells were isolated from human blood and stimulated in vitro. Flow cytometry were used to analyze the expression of PD-1. ELISA was used to measure the soluble form of PD-L1 in serum samples from RA patients and healthy controls. Quantitative PCR was used for transcriptional analysis of proteins and microRNAs involved in CD8+ T cell regulation. Microarray analysis of microRNA was performed in samples of human CD8+ T cells. Smokers had fewer activated CD8+ T cells that expressed PD-1 compared to non- smokers, and human CD8+ T cells stimulated with nicotine in vitro had lower expression of PD-1 messengerRNA. RA mice treated with nicotine had fewer PD-1 expressing CD8+ T cells in the bone marrow. This was related to the increased production and release in circulation of the onco-protein survivin, a predictive marker for severe RA. CD8+ T cells of smokers adopted a naïve/memory phenotype and had different expression of several microRNA that are involved in the regulation of memory T cell formation, including the FOXO signaling pathway. Smokers also had lower levels of soluble PD-L1 in serum. The low PD-L1 levels were linked to altered expression of antibody receptors on antigen-presenting cells producing soluble PD-L1. The presence of RA-specific autoantibodies was associated with serum levels of soluble PD-L1. I conclude that smoking interferes with the PD-1 inhibitory system on CD8+ T cells, which may contribute to higher risk for RA in smokers. This can occur because of the reduced inhibitory control of the CD8+ T cells with low PD-1 expression, but also because of a reduced supply of sPD-L1. Furthermore, I suggest that microRNA interfere with the FOXO signaling pathway and influence the phenotype of CD8+ T cells in smokers.
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| 15. |
- Wasén, Caroline, et al.
(författare)
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Smoking Is Associated With Low Levels of Soluble PD-L1 in Rheumatoid Arthritis
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is a risk factor for developing rheumatoid arthritis (RA), but the mechanism remains uncertain. We previously demonstrated that smoking lowers the T cell activation threshold by limiting programmed death protein 1 (PD-1) expression. Aim: To investigate how smoking influence the levels of soluble PD-1 ligand (sPD-L1). Method: Serum levels of sPD-L1 were measured in 246 RA patients and in 168 healthy subjects. The analysis was done with respect to inflammation, smoking, treatments, and autoantibody status. The effect of therapeutic TNF-inhibiting antibodies (TNFi) on sPD-L1 was studied in 16 RA patients at their first infliximab infusion. The expression of Fc gamma-receptor (Fc gamma R) subclass IIB and IIIA was analyzed with quantitative polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) from 12 RA patients and 15 healthy controls, and in healthy PBMC exposed to IgG containing antibodies to cyclic citrullinated peptides (aCCP). Results: The negative association between smoking and sPD-L1 in RA patients was established by multiple logistic regression (OR = 0.52, p = 0.038). Other covariates in the regression model were serum levels of IL-1 beta representing inflammation (OR = 1.6, p = 0.0076) and aCCP positivity (OR = 1.9, p = 0.047). First infliximab infusion repressed sPD-L1 (p = 0.023) in patients, and low levels of sPD-L1 were found in patients with early RA treated with TNFi (p = 0.018). Treatment with TNFi was associated with higher sPD-L1 in patients with long disease duration (p = 0.041) and restored levels in smokers. In vitro exposure to aCCP+ IgG suppressed sPD-L1 (p = 0.036), but aCCP+ patients with long disease duration had higher sPD-L1 (p = 0.016). High ratio of the inhibitory Fc gamma R subclass IIB over the stimulatory IIIA resulted in low sPD-L1 release (p = 0.029). Smoking was associated with a higher Fc gamma R IIB/IIIA ratio (p = 0.00062) and lower levels of sPD-L1 (p = 0.013). Conclusion: In RA, serum sPD-L1 was related to systemic inflammation and aCCP positivity. Smoking altered the expression of Fc gamma Rs and limited sPD-L1 in RA patients, permitting inappropriate T cell responses. Differential regulation of sPD-L1 during the early and late RA may indicate transposition from acute to chronic inflammation.
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| 16. |
- Wasén, Caroline, 1990, et al.
(författare)
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The emerging role of the microbiome in Alzheimer's disease
- 2022
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Ingår i: International Review of Neurobiology. - : Elsevier. - 2162-5514 .- 0074-7742. ; 167
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer's disease (AD) is the most prevalent form of dementia and can be influenced by genetic and environmental factors. Recent studies suggest that the intestinal microbiota is altered in AD patients when compared to healthy individuals and may play a role in disease onset and progression. Aging is the greatest risk factor for AD, and age-related changes in the microbiota can affect processes that contribute to cognitive decline. The microbiota may affect AD by modulating peripheral and central immunity or by secreting factors that influence neurogenesis or neuronal cell death. Finally, probiotic and dietary interventions that target the microbiome may have therapeutic potential to prevent or treat AD.
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| 17. |
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