| 21. |
- Kelkka, Tiina, et al.
(författare)
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Enhancement of antibody-induced arthritis via Toll-like receptor 2 stimulation is regulated by granulocyte reactive oxygen species
- 2012
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Ingår i: American Journal of Pathology. - New York, NY : Elsevier. - 0002-9440 .- 1525-2191. ; 181:1, s. 141-150
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Tidskriftsartikel (refereegranskat)abstract
- The suppressive role of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) complex-derived reactive oxygen species (ROS) in adaptive immunity-driven arthritis models is well established. In this study, we aimed to investigate the role of NOX2 complex-derived ROS in a model of innate immunity-driven arthritis and to identify the ROS-regulated innate receptors that control arthritis. We used collagen antibody-induced arthritis (CAIA), which is a T and B lymphocyte-independent model of the effector phase of arthritis and is induced by well-defined monoclonal arthritogenic antibodies and enhanced by injection of lipopolysaccharide (LPS). CAIA was induced in both wild-type and Ncf1 mutant mice that lack phagocyte oxidative burst, and stimulated with LPS and other agents to activate innate immune responses. We found that both LPS and lipomannan enhanced CAIA more potently in the presence of functional phagocyte ROS production than in its absence. The ROS-dependent enhancement of CAIA was regulated by TLR2, but not by TLR4 stimulation, and was driven by granulocytes, whereas macrophages did not contribute to the phenotype. In addition, we report that collagen-induced arthritis was not affected by the functionality of the TLR4. We report that TLR2 signaling as an important ROS-regulated proinflammatory pathway leads to severe neutrophil-dependent inflammation in murine CAIA and conclude that the TLR2 pathway is modulated by phagocyte ROS to stimulate the development of arthritis. © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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| 22. |
- Olofsson, Peter, et al.
(författare)
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Arthritis suppression by NADPH activation operates through an interferon-beta pathway
- 2007
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: A polymorphism in the activating component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (NCFI), has previously been identified as a regulator of arthritis severity in mice and rats. This discovery resulted in a search for NADPH oxidase- activating substances as a potential new approach to treat autoimmune disorders such as rheumatoid arthritis (RA). We have recently shown that compounds inducing NCFI- dependent oxidative burst, e. g. phytol, have a strong ameliorating effect on arthritis in rats. However, the underlying molecular mechanism is still not clearly understood. The aim of this study was to use gene- expression profiling to understand the protective effect against arthritis of activation of NADPH oxidase in the immune system. Results: Subcutaneous administration of phytol leads to an accumulation of the compound in the inguinal lymph nodes, with peak levels being reached approximately 10 days after administration. Hence, global gene- expression profiling on inguinal lymph nodes was performed 10 days after the induction of pristane-induced arthritis (PIA) and phytol administration. The differentially expressed genes could be divided into two pathways, consisting of genes regulated by different interferons. IFN-gamma regulated the pathway associated with arthritis development, whereas IFN-beta regulated the pathway associated with disease protection through phytol. Importantly, these two molecular pathways were also confirmed to differentiate between the arthritis-susceptible dark agouti (DA) rat, (with an Ncf-/(DA) allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-/(E3) rat (with an Ncf/(E3) allele that allows a stronger oxidative burst). Conclusion: Naturally occurring genetic polymorphisms in the Ncf-/ gene modulate the activity of the NADPH oxidase complex, which strongly regulates the severity of arthritis. We now show that the Ncf-/ allele that enhances oxidative burst and protects against arthritis is operating through an IFN-gamma-associated pathway, whereas the arthritis-driving allele operates through an IFN-gamma-associated pathway. Treatment of arthritis- susceptible rats with an NADPH oxidase- activating substance, phytol, protects against arthritis. Interestingly, the treatment led to a restoration of the oxidative- burst effect and induction of a strikingly similar IFN-beta-dependent pathway, as seen with the disease-protective Ncfl polymorphism.
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| 23. |
- Pizzolla, Angela, et al.
(författare)
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CD68-expressing cells can prime T cells and initiate autoimmune arthritis in the absence of reactive oxygen species.
- 2011
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 41:2, s. 403-412
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Tidskriftsartikel (refereegranskat)abstract
- It is widely believed that DC, but not macrophages, prime naïve T cells in vivo. Here, we investigated the ability of CD68-expressing cells (commonly defined as macrophages) in priming autoreactive T cells and initiating collagen-induced arthritis (CIA) in the mouse. For this purpose, a transgenic mouse was developed (MBQ mouse) where macrophages exclusively expressed the MHC class II H2-A(q) (A(q) ) on an H2-A(p) (A(p) ) background. A(q) , but not A(p) expression mediates susceptibility to CIA through presentation of type II collagen (CII) to T cells. CIA severity is enhanced by a mutation in the Ncf1 gene, impairing reactive oxygen species (ROS) production by the phagocyte NADPH oxidase (NOX2) complex. Expression of functional Ncf1 on macrophages was previously shown to protect from severe CIA. To study the effect of ROS on macrophage-mediated priming of T cells, the Ncf1 mutation was introduced in the MBQ mouse. Upon CII immunization, Ncf1-mutated MBQ mice, but not Ncf1 wild-type MBQ mice nor Ncf1-mutated A(p) mice, activated autoreactive T cells and developed CIA. These findings demonstrate for the first time that macrophages can initiate arthritis and that the process is negatively regulated by ROS produced via the NOX2 complex.
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| 24. |
- Pizzolla, A., et al.
(författare)
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Reactive Oxygen Species Produced by the NADPH Oxidase 2 Complex in Monocytes Protect Mice from Bacterial Infections
- 2012
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 188:10, s. 5003-5011
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Tidskriftsartikel (refereegranskat)abstract
- Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent life-threatening bacterial and fungal infections. CGD results from defective production of reactive oxygen species by phagocytes caused by mutations in genes encoding the NADPH oxidase 2 (NOX2) complex subunits. Mice with a spontaneous mutation in Ncf1, which encodes the NCF1 (p47(Phox)) subunit of NOX2, have defective phagocyte NOX2 activity. These mice occasionally develop local spontaneous infections by Staphylococcus xylosus or by the common CGD pathogen Staphylococcus aureus. Ncf1 mutant mice were more susceptible to systemic challenge with these bacteria than were wild-type mice. Transgenic Ncf1 mutant mice harboring the wild-type Ncf1 gene under the human CD68 promoter (MN+ mice) gained the expression of NCF1 and functional NOX2 activity specifically in monocytes/macrophages, although minimal NOX2 activity was also detected in some CD11b(+)Ly6G(+) cells defined as neutrophils. MN+ mice did not develop spontaneous infection and were more resistant to administered staphylococcal infections compared with MN- mice. Most strikingly, MN+ mice survived after being administered Burkholderia cepacia, an opportunistic pathogen in CGD patients, whereas MN- mice died. Thus, monocyte/macrophage expression of functional NCF1 protected against spontaneous and administered bacterial infections. The Journal of Immunology, 2012, 188: 5003-5011.
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| 25. |
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| 26. |
- Richter, Cornelia, et al.
(författare)
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Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:7, s. 4183-4191
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Tidskriftsartikel (refereegranskat)abstract
- Permanent exposure to pathogens requires decisions toward tolerance or immunity as a prime task of dendritic cells. The molecular mechanisms preventing uncontrolled immune responses are not completely clear. We investigated the regulatory function of Ncf1, an organizing protein of NADPH oxidase, in the signaling cascade of Toll-like receptors. TLR9-stimulated spleen cells from both Ncf1-deficient and B10.Q mice with a point mutation in exon 8 of Ncf1 exhibited increased IL-12p70 secretion compared with controls. This finding was restricted to stimulatory CpG2216 and not induced by CpG2088. Because only CpG/TLR9-induced IL-12p70 was regulated by Ncf1, we used TRIF-/- and MyD88(-/-) cells to show that TLR9/MyD88 was primarily affected. Interestingly, additional experiments revealed that spleen cells from NOX2/gp91(phox)-deficient mice and the blocking of electron transfer by diphenylene iodonium had no influence on CpG-induced IL-12p70, confirming an NADPH oxidase-independent function of Ncf1. Finally, proving the in vivo relevance CpG adjuvant-guided OVA immunization resulted in a strong augmentation of IL-12p70-dependent Th1 IFN-gamma response only in Ncf1-deficient mice. These data suggest for the first time an important role for Ncf1 in, the fine tuning of the TLR9/MyD88 pathway in vitro and in vivo that is independent of its role as an activator of NOX2. The Journal of Immunology, 2009,182: 4183-4191.
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| 27. |
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| 28. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Collagen type II and a thermo-responsive polymer of N-isopropylacrylamide induce arthritis independent of Toll-like receptors : a strong influence by major histocompatibility complex class II and Ncf1 genes
- 2011
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Ingår i: American Journal of Pathology. - New York : Elsevier. - 0002-9440 .- 1525-2191. ; 179:5, s. 2490-2500
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Tidskriftsartikel (refereegranskat)abstract
- We established and characterized an arthritis mouse model using collagen type II (CII) and a thermo-responsive polymer, poly(N-isopropylacrylamide) (PNiPAAm). The new PNiPAAm adjuvant is TLR-independent, as all immunized TLR including MyD88-deficient mice developed an anti-CII response. Unlike other adjuvants, PNiPPAm did not skew the cytokine response (IL-1beta, IFN-gamma, IL-4, and IL-17), as there was no immune deviation towards any one type of immune spectrum after immunization with CII/PNiPPAm. Hence, using PNiPAAm, we studied the actual immune response to the self-protein, CII. We observed arthritis and autoimmunity development in several murine strains having different major histocompatibility complex (MHC) haplotypes after CII/PNiPAAm immunization but with a clear MHC association pattern. Interestingly, C57Bl/6 mice did not develop CII-induced arthritis, with PNiPAAm demonstrating absolute requirement for a classical adjuvant. Presence of a gene (Ncf1) mutation in the NADPH oxidation complex has a profound influence in arthritis and using PNiPAAm we could show that the high CIA severity in Ncf1 mutated mice is independent of any classical adjuvant. Macrophages, neutrophils, eosinophils, and osteoclasts but not mast cells dominated the inflamed joints. Furthermore, arthritis induction in the adjuvant-free, eosinophil-dependent Vbeta12 DBA/1 mice could be shown to develop arthritis independent of eosinophils using CII/PNiPAAm. Thus, biocompatible and biodegradable PNiPAAm offers unique opportunities to study actual autoimmunity independent of TLR and a particular cytokine phenotype profile.
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| 29. |
- Tuncel, Jonatan, et al.
(författare)
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Self-reactive T cells induce and perpetuate chronic relapsing arthritis
- 2020
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: CD4+ T cells play a central role during the early stages of rheumatoid arthritis (RA), but to which extent they are required for the perpetuation of the disease is still not fully understood. The aim of the current study was to obtain conclusive evidence that T cells drive chronic relapsing arthritis. Methods: We used the rat pristane-induced arthritis model, which accurately portrays the chronic relapsing-remitting disease course of RA, to examine the contribution of T cells to chronic arthritis. Results: Rats subjected to whole-body irradiation and injected with CD4+ T cells from lymph nodes of pristane-injected donors developed chronic arthritis that lasted for more than 4 months, whereas T cells from the spleen only induced acute disease. Thymectomy in combination with irradiation enhanced the severity of arthritis, suggesting that sustained lymphopenia promotes T cell-driven chronic inflammation in this model. The ability of T cells to induce chronic arthritis correlated with their expression of Th17-associated transcripts, and while depletion of T cells in rats with chronic PIA led to transient, albeit significant, reduction in disease, neutralization of IL-17 resulted in almost complete and sustained remission. Conclusion: These findings show that, once activated, self-reactive T cells can sustain inflammatory responses for extended periods of time and suggest that such responses are promoted in the presence of IL-17.
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| 30. |
- Wallner, Fredrik K., et al.
(författare)
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Cytokine correlation analysis based on drug perturbation
- 2017
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Ingår i: Cytokine. - : Elsevier. - 1043-4666 .- 1096-0023. ; 90, s. 73-79
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Tidskriftsartikel (refereegranskat)abstract
- Cytokines and chemokines play a crucial role in regulating the immune system. Understanding how these molecules are co-regulated is important to understand general immunology, and particularly their role in clinical applications such as development and evaluation of novel drug therapies. Cytokines are today widely used as therapeutic targets and as biomarkers to monitor effects of drug therapies and for prognosis and diagnosis of diseases. Therapies that target a specific cytokine are also likely to affect the production of other cytokines due to their cross-regulatory functions and because the cytokines are produced by common cell types. In this study, we have perturbated the production of 17 different cytokines in a preclinical rat model of autoimmune arthritis, using 55 commercially available immunomodulatory drugs and clinical candidates. The majority of the studied drugs was selected for their anti-inflammatory role and was confirmed to inhibit the production of IL-2 and IFN-γ in this model but was also found to increase the production of other cytokines compared to the untreated control. Correlation analysis identified 58 significant pairwise correlations between the cytokines. The strongest correlations found in this study were between IL-2 and IFN-γ (r=0.87) and between IL-18 and EPO (r=0.84). Cluster analysis identified two robust clusters: (1) IL-7, IL-18 and EPO, and (2) IL-2, IL-17 and IFN-γ. The results show that cytokines are highly co-regulated, which provide valuable information for how a therapeutic drug might affect clusters of cytokines. In addition, a cytokine that is used as a therapeutic biomarker could be combined with its related cytokines into a biomarker panel to improve diagnostic accuracy.
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