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| 2. |
- Andersson, Karin, 1972, et al.
(author)
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Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment.
- 2015
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In: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 21, s. 536-43
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Journal article (peer-reviewed)abstract
- T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.
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| 3. |
- Andersson, Karin, 1972, et al.
(author)
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Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6
- 2015
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:24, s. 20043-20057
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Journal article (peer-reviewed)abstract
- Follicular T helper (Tfh) cells are recognized by the expression of CXCR5 and the transcriptional regulator Bcl-6. Tfh cells control B cell maturation and antibody production, and if deregulated, may lead to autoimmunity. Here, we study the role of the proto-oncogene survivin in the formation of Tfh cells. We show that blood Tfh cells of patients with the autoimmune condition rheumatoid arthritis, have intracellular expression of survivin. Survivin was co-localized with Bcl-6 in the nuclei of CXCR5(+)CD4 lymphocytes and was immunoprecipitated with the Bcl-6 responsive element of the target genes. Inhibition of survivin in arthritic mice led to the reduction of CXCR5(+) Tfh cells and to low production of autoantibodies. Exposure to survivin activated STAT3 and induced enrichment of PD-1(+)Bcl-6(+) subset within Tfh cells. Collectively, our study demonstrates that survivin belongs to the Tfh cell phenotype and ensures their optimal function by regulating transcriptional activity of Bcl-6.
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| 5. |
- Cavallini, Nicola, 1978
(author)
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Acute and chronic peritonitis in peritoneal dialysis: neurogenic inflammation and citrate treatment
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The prevalent problems associated with peritoneal dialysis (PD) are ultrafiltration failure and peritonitis. During PD the patient is sustained on a state of intraperitoneal inflammation, which over time impairs structure, and function of the peritoneal membrane, leading to loss of ultrafiltration efficacy. The aims of this project was: to establish whether neurogenic inflammation and mast cell activation are triggered by PD fluid exposure and to evaluate the effects of citrate as an additive to PD fluid in acute and chronic animal models. The studies were conducted in rats, exposed to filter sterilised lactate or lactate/citrate buffered PD fluid with glucose (2.5 and 3.9 %) as osmotic agent through an implanted catheter. Acute studies were based on single exposure and long-term studies on daily exposures for a period of 5 weeks. Pharmacological intervention was used to study mast cell activation and the neurogenic inflammatory response. Histamine was released into the peritoneal cavity within 30 minutes of infusion of standard PD fluid. Also osmotically neutral fluid triggered a histamine release from mast cells. Indirect evidence for the release of neuropeptides SP and CGRP suggested actions of a neurogenic inflammation. Mast cell activation was shown to be dependent on substance P stimulation of its receptor, NK-1. Inhibiting NK-1 significantly reduced vascular albumin loss from the blood to the peritoneal cavity by a mast cell independent mechanism. Blocking CGRP resulted in a significant increase in osmotic and net ultrafiltration. The classic trigger of neuropeptide release, the TRPV1 receptor was, unexpectedly, not responsible for neuropeptide actions in the present model. Substituting 5-15 mM lactate with equal amounts of citrate gradually improved osmotic ultrafiltration (fluid transport) compared with lactate PD fluid, suggesting a dose-response relationship. Significantly improved net ultrafiltration (fluid gain) was the result of increased osmotic ultrafiltration, in response to 10 - 15 mM citrate substitution. Long-term treatment with citrate-substituted PD fluid in rats did not significantly reduce fibrosis and angiogenesis of the peritoneal membrane compared with standard PD fluid. PD catheter patency was, however, significantly improved in animals treated with citrate substituted PD fluid. Macroscopic signs of fibrosis were also significantly reduced by citrate. The clinical implications are that pharmacological intervention with the neurogenic inflammatory response and calcium chelation with citrate have potential to improve the efficiency of peritoneal dialysis.
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| 9. |
- Cavallini, Nicola, 1978, et al.
(author)
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Neuropeptide release augments serum albumin loss and reduces ultrafiltration in peritoneal dialysis
- 2012
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In: Peritoneal Dialysis International. - : SAGE Publications. - 0896-8608 .- 1718-4304. ; 32:2, s. 168-176
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Journal article (peer-reviewed)abstract
- Background: The triggers of the acute local inflammatory response to peritoneal dialysis (PD) fluid exposure remain unknown. In the present study, we investigated the effects of neurogenic inflammation and mast cell degranulation on water and solute transport in experimental PD. Methods: Single 2-hour dwells in rats with PD catheters were studied. Histamine and the neuropeptides substance P and calcitonin gene-related peptide (CGRP) were measured in PD fluid samples by ELISA. Radiolabeled albumin (I-125 and I-131 respectively) was used as an intraperitoneal (IP) and intravascular tracer. Glucose and urea concentrations were measured in plasma and PD fluid. The effects of varying the volume and osmolarity of a lactate-buffered PD fluid were compared and related to the effects of pharmacologic intervention. Results: Application of 20 mL 3.9% glucose PD fluid induced an IP histamine release during the first 30 minutes, blockable by the mast cell stabilizer doxantrazole and the substance P neurokinin-1 receptor (NK1R)-blocker spantide. Histamine release was also inhibited at a reduced PD volume (14 mL), but was not affected by normalizing the PD fluid osmolarity. Blockade of NK1R also reduced plasma albumin leakage to the peritoneal cavity. Inhibition of CGRP receptors by CGRP8-37 improved osmotic (transcapillary) and net ultrafiltration and reduced the dialysate urea concentration. Neuropeptide release was not clearly related to activation of the TrpV1 receptor, the classic trigger of neurogenic inflammation. Conclusions: Neuropeptide release exaggerated albumin loss and reduced ultrafiltration in this rat PD model. Intervention aimed at the neuropeptide action substantially improved PD efficiency.
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| 10. |
- Cavallini, Nicola, 1978, et al.
(author)
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Substituting citrate for lactate in peritoneal dialysis fluid improves ultrafiltration in rats
- 2009
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In: Peritoneal Dialysis International. - 0896-8608. ; 29:1, s. 36-43
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Journal article (peer-reviewed)abstract
- BACKGROUND: Exposure to peritoneal dialysis (PD) fluid induces an inflammatory response in the peritoneal cavity. Blockers of complement and coagulation have improved ultrafiltration in animal models of PD. Citrate is a clinically established anticoagulant that also blocks complement activation. OBJECTIVE: The aim of the present study was to evaluate the effects on ultrafiltration of a gradual substitution of citrate for lactate in an experimental model of PD. METHODS: Fractions (0, 5, 10, and 15 mmol/L) of the 40 mmol/L lactate buffer of filter-sterilized 2.5% glucose PD fluid were replaced by citrate. The modified fluids were compared in a rat model of single PD fluid exposure through an indwelling catheter. The initial kinetics of citrate and ionized calcium were evaluated in separate, single, short time dwell experiments. RESULTS: Replacing 10 and 15 mmol/L of the lactate buffer by sodium citrate significantly increased osmotic ultrafiltration (by 24.7%+/-7.7% at 10 mmol/L), net ultrafiltration, and glucose retention at 4 hours of dwell time in the rat model. Osmotic ultrafiltration was significantly correlated to citrate concentration and glucose concentration. Citrate was rapidly eliminated from the peritoneal cavity, concentrations falling to less than half in 1 hour and concentrations of calcium ions concomitantly normalized. CONCLUSIONS: Substituting citrate for lactate induced a dose-dependent increase in ultrafiltration. Mechanisms probably involve the relation between diffusion and ultrafiltration, leading to increased glucose retention. The increase in ultrafiltration was quantitatively important at a citrate concentration (10 mmol/L) that is compatible with clinical applications of citrate.
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