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Rikard Holmdahl - One of the best experts on this subject based on the ideXlab platform.
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Self-reactive T cells induce and perpetuate chronic relapsing Arthritis.
Arthritis Research & Therapy, 2020Co-Authors: Jonatan Tuncel, Jens Holmberg, Peter Olofsson, Sabrina Haag, Malin Hultqvist Hopkins, Lena Wester-rosenlöf, Stefan Carlsen, Rikard HolmdahlAbstract: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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MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early Arthritis in a rat model of rheumatoid Arthritis.
European Journal of Immunology, 2017Co-Authors: Jonatan Tuncel, Sabrina Haag, Rikard HolmdahlAbstract:Polymorphisms in the MHC class II (MHCII) genes are strongly associated with rheumatoid Arthritis, supporting the importance of autoreactive T helper (Th) cells for the development of this disease. Here, we used Pristane-Induced Arthritis (PIA), induced by the non-antigenic hydrocarbon pristane, to study the impact of different MHCII alleles on T-cell activation and differentiation. In MHCII-congenic rats with disease-promoting MHCII alleles, pristane primarily induced activation of Th1 cells, whereas activated T cells were Th17 biased in rats with protective MHCII alleles. Neutralization of IFN-γ during T-cell activation abrogated the development of disease, suggesting that Th1 immunity is important for disease induction. Neutralization of IL-17, by contrast, suppressed Arthritis only when performed in rats with established disease. Adoptive T-cell transfers showed that T cells acquired arthritogenic capacity earlier in strains with a prevailing Th1 response. Moreover, upon pristane injection, these strains exhibited more Ag-primed OX40+ and proliferating T cells of polyclonal origin. These data show that T cells are polarized upon the first encounter with peptide-MHCII complexes in an allele-dependent fashion. In PIA, the polyclonal expansion of autoreactive Th1 cells was necessary for the onset of Arthritis, while IL-17 mediated immunity contributed to the progression to chronic disease. This article is protected by copyright. All rights reserved
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pristane induces autophagy in macrophages promoting a stat1 irf1 tlr3 pathway and Arthritis
Clinical Immunology, 2017Co-Authors: Jing Xu, Qilan Ning, Congshan Jiang, Manman Geng, Nazim Hussain, Dongmin Li, Xiaoying Wu, Fujun Zhang, Bo Wang, Rikard HolmdahlAbstract:Abstract Autophagy is involved in both innate and adaptive immune regulation. We propose that autophagy regulates activation of TLR3 in macrophages and is thereby essential for development of Pristane-Induced Arthritis. We found that pristane treatment induced autophagy in macrophages in vitro and in vivo, in spleen cells from pristane injected rats. The induced autophagy was associated with STAT1 phosphorylation and expression of IRF1 and TLR3. Blocking the pristane activated autophagy by Wortmannin and Bafilomycin A1 or by RNAi of Becn1 led to a downregulation of the associated STAT1-IRF1-TLR3 pathway. Most importantly, the development of Arthritis was alleviated by suppressing either autophagy or TLR3. We conclude that pristane enhanced autophagy, leading to a STAT1-IRF1 controlled upregulation of TLR3 expression in macrophages, is a pathogenic mechanism in the development of Arthritis.
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Positional Identification of RT1-B (HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis
Journal of Immunology, 2015Co-Authors: Sabrina Haag, Jonatan Tuncel, Johan Backlund, Soley Thordardottir, Daniel E. Mason, Doreen Dobritzsch, Eric C. Peters, Rikard HolmdahlAbstract:Rheumatoid Arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is Pristane-Induced Arthritis (PIA) in the rat where polyclonal T cells induce chronic Arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that Arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.
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pristane primed rat t cells enhance tlr3 expression of fibroblast like synoviocytes via tnf α initiated p38 mapk and nf κb pathways
Clinical Immunology, 2015Co-Authors: Congshan Jiang, Manman Geng, Xiaoying Wu, Rikard Holmdahl, Jing Xu, Liesu Meng, Shemin LuAbstract:Abstract Based on Pristane-Induced Arthritis (PIA), we found that T cells mediate TLR3 overexpression in fibroblast-like synoviocytes (FLS). The aim of this study is to determine key factors by which T cells induce TLR3 expression. Rat FLS were co-cultured with pristane primed T cell conditioned medium (PPT medium), and TLR3 expression of FLS was significantly induced. TNF-α, IFN-γ and IL-17 were dominantly expressed in PIA T cells. The overexpression of TLR3 and its related genes in FLS co-cultured with PPT medium could be reduced through blocking TNF-α pathway. CD4+ T cells from spleen of PIA rats showed increase of TNF-α secretion. P38 MAPK and NF-κB were activated in FLS by PPT medium, and their inhibitors decreased TLR3 upregulation significantly. Finally, TNF-α induced TLR3 expression was confirmed in human synovial cells. Summarily, TNF-α derived from pristane primed T cells induced TLR3 expression of FLS through activating p38 MAPK and NF-κB pathways.
Shemin Lu - One of the best experts on this subject based on the ideXlab platform.
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Increased expression of Th17 cytokines and interleukin-22 correlates with disease activity in Pristane-Induced Arthritis in rats.
PLOS ONE, 2017Co-Authors: Bo Wang, Congshan Jiang, Liesu Meng, Yan Zhou, Panpan Zhao, Linyu Wang, Shemin LuAbstract:: The objective of this study was to identify the key changed subtype of T helper cells (Th cells) and their cytokines in Pristane-Induced Arthritis (PIA) in rats. The severity of Arthritis was evaluated by body weight, clinical score, the perimeter of ankle and mid-paw and histological assessment of ankle joints. Cytokines of Th1, Th2 and Th17 were determined in the spleen and inguinal lymph nodes at 28 days after pristane injection by real-time qPCR. The mRNA levels of IL-22 receptors, IL-22R1 and IL-22BP, in the spleen were quantified by real-time qPCR. Additionally, IL-22 expression in synovial membrane was detected by Western blotting, and serum IL-22 concentration was determined by ELISA. Correlation between IL-22 concentration and clinical score was analyzed. By screening the cytokines of Th1, Th2 and Th17 expression profile, we found that the mRNA levels of Th17 cytokines were significantly increased in PIA rats. Particularly, a significant increase in the protein expression of IL-22 was determined in synovial membrane and serum from PIA rats, and correlated with clinical score. We conclude that IL-22 expression level was increased and correlated with disease severity, which indicated that IL-22 may play an important role in development of PIA, and was helpful to explorer the pathogenesis of rheumatoid Arthritis.
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IL‑22 expression is increased variedly in the initial phase, onset and chronic phase of a pristane‑induced Arthritis rat model
Molecular Medicine Reports, 2017Co-Authors: Bo Wang, Congshan Jiang, Liesu Meng, Yan Zhou, Ke Xu, Peng Xu, Shemin LuAbstract:: The aim of the present study was to investigate the expression pattern of T helper (Th) 17 and Th22 cell-related factors in a pristane‑induced Arthritis (PIA) rat model. PIA rats were divided into the initial phase group [day (D) 6 post‑pristane injection], the onset of clinical Arthritis group (D12), the acute Arthritis group (D26) and the chronic Arthritis group (D70). Rats injected with saline alone were used as the control group. The mRNA expression levels of interleukin (IL)‑17A, IL‑17F, interferon (IFN)‑γ, IL‑22, IL‑22 receptor (R) 1, IL‑22 binding protein (BP) and RAR‑related orphan receptor α were examined in the spleen and/or synovium of the various phases of PIA rats by reverse transcription‑quantitative polymerase chain reaction analysis. The results demonstrated that, in the spleen, IL‑22 exhibited an increasing trend in both the initial phase and the onset of disease, while the ratio of IL‑22R1/IL‑22BP increased in both phases, compared with the control group. During the acute Arthritis phase, IL‑17F and IFN‑γ were significantly increased and IL‑17A exhibited an increasing tendency in the synovium, compared with the control group. In the chronic phase, IL‑22, IL‑22R1 and IFN‑γ were increased in the spleen, while IL‑22 exhibited an increasing trend in the synovium. In addition, immunohistochemistry analysis was used to evaluate the expression of IL‑17A, IL‑21, IL‑22 and IL‑22R1 in the ankle joints of D26 PIA rats. IL‑17A was mainly expressed in infiltrated inflammatory cells in the synovium. IL‑21 and IL‑22 were both expressed in the inflammatory cells and in the articular chondrocyte of the proliferative zone. IL‑22R1 was expressed in proliferating synovial cells. In conclusion, Th17 and Th22‑related factor expression varied in different disease progression phases and in different tissues in PIA rats. IL‑22 expression exhibited an increasing trend in the initial phase and the onset phase of Arthritis and increased significantly with progression to chronic Arthritis in the PIA rat model. It is thought that IL‑22 may serve an important role in the pathological process of PIA, particularly in the chronic fluctuation phase. Therefore, it may be a candidate molecule for the treatment of rheumatoid Arthritis.
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pristane primed rat t cells enhance tlr3 expression of fibroblast like synoviocytes via tnf α initiated p38 mapk and nf κb pathways
Clinical Immunology, 2015Co-Authors: Congshan Jiang, Manman Geng, Xiaoying Wu, Rikard Holmdahl, Jing Xu, Liesu Meng, Shemin LuAbstract:Abstract Based on Pristane-Induced Arthritis (PIA), we found that T cells mediate TLR3 overexpression in fibroblast-like synoviocytes (FLS). The aim of this study is to determine key factors by which T cells induce TLR3 expression. Rat FLS were co-cultured with pristane primed T cell conditioned medium (PPT medium), and TLR3 expression of FLS was significantly induced. TNF-α, IFN-γ and IL-17 were dominantly expressed in PIA T cells. The overexpression of TLR3 and its related genes in FLS co-cultured with PPT medium could be reduced through blocking TNF-α pathway. CD4+ T cells from spleen of PIA rats showed increase of TNF-α secretion. P38 MAPK and NF-κB were activated in FLS by PPT medium, and their inhibitors decreased TLR3 upregulation significantly. Finally, TNF-α induced TLR3 expression was confirmed in human synovial cells. Summarily, TNF-α derived from pristane primed T cells induced TLR3 expression of FLS through activating p38 MAPK and NF-κB pathways.
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microrna 26a negatively regulates toll like receptor 3 expression of rat macrophages and ameliorates pristane induced Arthritis in rats
Arthritis Research & Therapy, 2014Co-Authors: Congshan Jiang, Qilan Ning, Jing Xu, Bo Wang, Liesu Meng, Rui Zhang, Nannan Zhong, Hongchuan Yu, Shemin LuAbstract:Introduction Abnormal toll-like receptor (TLR)3 signaling plays an indispensable role in pathogenesis of both experimental and human rheumatoid Arthritis, and microRNAs (miRNAs) might orchestrate this signaling pathway. This study was performed to determine the relationship between miR-26a and TLR3 in rat macrophages and to observe effects of miR-26a mimic on pristane induced Arthritis (PIA) in rats.
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Induction of toll-like receptor 2 positive antigen-presenting cells in spleen of Pristane-Induced Arthritis in rats.
Molecular Biology Reports, 2011Co-Authors: Liesu Meng, Congshan Jiang, Jing Xu, Bo Wang, Shemin LuAbstract:Toll-like receptors (TLRs) have been found to contribute to the pathogenesis of rheumatoid Arthritis (RA). The aim of this study is to investigate the regulation and potential role of TLR2 in spleen of Pristane-Induced Arthritis (PIA) rat, which can be used to further understand the mechanisms of RA. Arthritis in DA rats was induced by pristane. TLR2 expression in spleen was detected by real-time quantitative PCR and western blotting, and TLR2 expression at both mRNA and protein levels was upregulated in PIA rats. Peptidoglycan (PGN) was systemically administrated to PIA rats, and Arthritis severity was evaluated macroscopically and microscopically. Results showed that systemic administration of PGN to PIA rats obviously deteriorated Arthritis severity. TLR2 expression on splenocytes and different types of immune cells was measured by flow cytometry. And it was found that TLR2 was mainly expressed on antigen-presenting cells (APCs) of spleen, and the proportion of TLR2+ dendritic cells and macrophages in spleen of PIA rats was increased remarkably. Thus, we conclude that the induction of TLR2+ APCs in spleen may participate in the maintenance of PIA.
Pércio S. Gulko - One of the best experts on this subject based on the ideXlab platform.
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RTD-1 therapeutically normalizes synovial gene signatures in rat autoimmune Arthritis and suppresses proinflammatory mediators in RA synovial fibroblasts.
Physiological Genomics, 2019Co-Authors: Prasad Tongaonkar, Teresina Laragione, Pércio S. Gulko, Vasu Punj, Akshay Subramanian, Dat Tran, Katie K. Trinh, Justin B. Schaal, Andre J. Ouellette, Michael E. SelstedAbstract:Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in Pristane-Induced Arthritis (PIA) in rats, a model of rheumatoid arthri...
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Arthritis severity locus Cia4 is an early regulator of IL-6, IL-1β, and NF-κB activators' expression in Pristane-Induced Arthritis
Physiological Genomics, 2013Co-Authors: Max Brenner, Teresina Laragione, Pércio S. GulkoAbstract:Cia4 is a locus on rat chromosome 7 that regulates disease severity and joint damage in models of rheumatoid Arthritis, including Pristane-Induced Arthritis (PIA). To identify molecular processes r...
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the Arthritis severity locus cia5a regulates the expression of inflammatory mediators including syk pathway genes and proteases in pristane induced Arthritis
BMC Genomics, 2012Co-Authors: Max Brenner, Pércio S. GulkoAbstract:Cia5a is a locus on rat chromosome 10 that regulates disease severity and joint damage in two models of rheumatoid Arthritis, collagen- and Pristane-Induced Arthritis (PIA). In this study, we aimed to identify cellular and molecular processes regulated by Cia5a using microarray-based gene expression analysis of synovial tissues from MHC identical DA (severe erosive disease) and DA.F344(Cia5a) congenics (mild non-erosive disease) rats. Synovial tissues from six DA and eight DA.F344(Cia5a) rats were analyzed 21 days after the induction of PIA using the Illumina RatRef-12 BeadChip (21,922 genes) and selected data confirmed with qPCR. There was a significantly increased expression of pro-inflammatory mediators such as Il1b (5-fold), Il18 (3.9-fold), Cxcl1 (10-fold), Cxcl13 (7.5-fold) and Ccl7 (7.9-fold), and proteases like Mmp3 (23-fold), Mmp9 (32-fold), Mmp14 (4.4-fold) and cathepsins in synovial tissues from DA, with reciprocally reduced levels in congenics. mRNA levels of 47 members of the Spleen Tyrosine Kinase (Syk) pathway were significantly increased in DA synovial tissues compared with DA.F344(Cia5a), and included Syk (5.4-fold), Syk-activating receptors and interacting proteins, and genes regulated by Syk such as NFkB, and NAPDH oxidase complex genes. Nuclear receptors (NR) such as Rxrg, Pparg and Rev-erba were increased in the protected congenics, and so was the anti-inflammatory NR-target gene Scd1 (54-fold increase). Tnn (72-fold decrease) was the gene most significantly increased in DA. Analyses of gene expression in synovial tissues revealed that the Arthritis severity locus Cia5a regulates the expression of key mediators of inflammation and joint damage, as well as the expression of members of the Syk pathway. This expression pattern correlates with disease severity and joint damage and along with the gene accounting for Cia5a could become a useful biomarker to identify patients at increased risk for severe and erosive disease. The identification of the gene accounting for Cia5a has the potential to generate a new and important target for therapy and prognosis.
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The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology
Molecular Medicine, 2012Co-Authors: Teresina Laragione, Anish Shah, Pércio S. GulkoAbstract:Serum levels of vitamin D levels are commonly reduced in patients with rheumatoid Arthritis (RA) and have been implicated in disease pathogenesis. We recently identified a new vitamin D receptor transcriptional signature in synovial tissues from rats with mild and nonerosive Arthritis, suggesting a vitamin D-mediated protective effect. In the present study, we address the hypothesis that part of the vitamin D protective effect is mediated via interference with fibroblast-like synoviocyte (FLS) invasive properties, an in vitro cellular phenotype that correlates with radiographic and histological damage in Pristane-Induced Arthritis and RA. FLSs derived from DA rats with Pristane-Induced Arthritis and RA patients were studied in an in vitro model of invasion through a collagen-rich barrier (Matrigel) over a 24-h period, in the presence or absence of calcitriol, an active form of vitamin D. Matrix metalloprotease (MMP) expression levels were analyzed with zymography and quantitative real-time polymerase chain reaction, and the cytoskeleton was studied with immunofluorescense microscopy. Calcitriol significantly inhibited DA and RA FLS invasion by 54% and 53%, respectively. Calcitriol also reduced interleukin (IL)-1β-induced expression of MMP-1 by 95% in DA FLSs and by 73.5% in RA FLS. Calcitriol treatment reduced actin cytoskeleton reorganization, reduced polarized formation of lamellipodia and reduced colocalization of phosphorylated focal adhesion kinase (p-FAK) with lamellipodia, all consistent with reduced cell ability to move and invade. In conclusion, we identified a new effect of calcitriol in FLS invasion. This discovery suggests that the reduced serum levels of vitamin D and its metabolites commonly seen in RA might increase risk for FLS-mediated cartilage and bone invasion and erosions. Treatment with vitamin D or its analogs has the potential to become a helpful adjuvant aimed at preventing or reducing joint destruction.
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Synovial expression of Th17-related and cancer-associated genes is regulated by the Arthritis severity locus Cia10.
Genes and Immunity, 2011Co-Authors: E Jenkins, Max Brenner, Teresina Laragione, Pércio S. GulkoAbstract:We have previously identified Cia10 as an Arthritis severity and articular damage quantitative trait locus. In this study we used Illumina RatRef-12 microarrays to analyze the expression of 21,922 genes in synovial tissues from Arthritis-susceptible DA and Arthritis-protected DA.ACI(Cia10) congenics with Pristane-Induced Arthritis. 310 genes had significantly different expression. The genes up-regulated in DA, and reciprocally down-regulated in DA.ACI(Cia10) included IL-11, Ccl12 and Cxcl10, as well as genes implicated in Th17 responses such as IL-17A, IL-6, Ccr6, Cxcr3 and Stat4. Suppressors of immune responses Tgfb and Vdr, and inhibitors of oxidative stress were up-regulated in congenics. There was an over-representation of genes implicated in cancer and cancer-related phenotypes such as tumor growth and invasion among the differentially expressed genes. Cancer-favoring genes like Ctsd, Ikbke, and Kras were expressed in increased levels in DA, while inhibitors of cancer phenotypes such as Timp2, Reck and Tgfbr3 were increased in DA.ACI(Cia10). These results suggest that Cia10 may control Arthritis severity, synovial hyperplasia and joint damage via the regulation of the expression of cancer-related genes, inflammatory mediators and Th17-related markers. These new findings have the potential to generate new targets for therapies aimed at reducing Arthritis severity and joint damage in rheumatoid Arthritis.
Christopher J. Elson - One of the best experts on this subject based on the ideXlab platform.
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Mediators of joint swelling and damage in rheumatoid Arthritis and pristane induced Arthritis.
Autoimmunity, 2009Co-Authors: Christopher J. Elson, Stephen J. Thompson, C. I. Westacott, K. D. BhoolaAbstract:Joint swelling and tenderness in rheumatoid Arthritis (RA) probably result from IgG aggregates activating complement with the consequent attraction of polymorphonuclear leucocytes (PMNs) and the liberation of their granule enzymes such as kininogenases. By contrast IL-1 and TNF are the major stimulants of cartilage and bone loss although other agents contribute. The fundamental drive for the production of these mediators is unknown but a role for heat shock proteins is suggested from work on pristane induced Arthritis.
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Modulation of Pristane-Induced Arthritis by mycobacterial antigens.
Autoimmunity, 2009Co-Authors: Stephen J. Thompson, Graham A. W. Rook, P. D. Butcher, V. K. R. Patel, Jl Stanford, Christopher J. ElsonAbstract:Several prominent mycobacterial protein antigens involved in antibody and T cell responses have been identified as members of highly conserved heat shock protein families. In particular, immune responses to the mycobacterial 65 kD heat shock protein (hsp65) have been implicated in the pathogenesis of autoimmune diseases both in experimental animal models and in man. Additionally, hsp65 has been shown to modulate the course of autoimmune disease in such experimental animal systems. In this report, we have examined the synthesis of heat shock proteins by a fast growing mycobacterial strain, M. vaccae, in heat stressed cultures and used the pristane induced Arthritis model to investigate the immunoprophylactic and immunotherapeutic potential of heat killed M. vaccae.Heat shock of M. vaccae cultures at 48°C demonstrated a 43-fold increase in hsp65 over that expressed at 37°C. It is therefore suggested that heat killed M. vaccae contains sufficient hsp that can be presented in the context of appropriate adjuva...
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Cellular And Humoral Reactivity Pattern To The Mycobacterial Heat Shock Protein hsp65 In Pristane Induced Arthritis Susceptible And hsp65 Protected DBA/1 Mice
Autoimmunity, 2009Co-Authors: Stephen J. Thompson, Yasuo Hitsumoto, M. Ghoraishian, Christopher J. ElsonAbstract:We have analysed the cellular and humoral immunity to the mycobacterial 65 kD heat shock protein (hsp65) in groups of DBA/1 mice with Arthritis induced by intraperitoneal injection of the mineral oil pristane. Here we confirm that DBA/1 mice are highly susceptible to pristane induced Arthritis (PIA) and demonstrate that the incidence of Arthritis can be modulated by either pretreatment with low dose irradiation or by preimmu-nisation with recombinant hsp65. Global cellular responses to antigens such as BSA or type II collagen were not enhanced or impaired within groups of arthritic (A) or non-arthritic (NA) mice. However, the cellular response to hsp65 in arthritic animals preimmunised with the 65 kD antigen was significantly elevated in comparison to hsp65 preimmunised mice that were resistant to the induction of disease. On the contrary, the level of hsp65 specific antibodies was much high in NA animals than in PIA mice. CBA/Igb mice are partially susceptible to the induction of PIA. We have previously ...
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Differential effects of immunisation with mycobacterial 65 kD heat shock protein on two models of autoimmunity.
Autoimmunity, 2009Co-Authors: Robert N. Barker, Stephen J. Thompson, M. Ghoraishian, G. R. Webb, F. M. Ponsford, Christopher J. ElsonAbstract:The effects of preimmunisation with the 65 kD mycobacterial heat shock protein (hsp65) on 2 murine models of autoimmunity were compared. Experimental autoimmune haemolytic anaemia (AIHA) can be provoked in mice by repeated injection with rat red blood cells (RBC). In this model, preimmunisation with hsp65 10 days before induction of disease resulted in a partial. but significant, reduction in RBC-bound autoantibody levels measured by Coombs' test. However, preimmunisation with human IgG (hIgG) was associated with a similar suppressive effect. Administration of neither hsp65 nor hIgG affected the direct or indirect anti-rat agglutinin titres of mice subsequently injected with rat RBC. Injection of hsp65 or hIgG prior to induction of AIHA elicited the production of IgG antibodies against the respective immunogen, as judged by enzyme-linked immunosorbent assays. In contrast to the results in experimental AIHA, Pristane-Induced Arthritis (PIA) was effectively prevented by preimmunisation with hsp65, but not w...
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agalactosyl igg in pristane induced Arthritis pregnancy affects the incidence and severity of Arthritis and the glycosylation status of igg
Clinical and Experimental Immunology, 2008Co-Authors: S J Thompson, Yasuo Hitsumoto, Yan W Zhang, Graham A. W. Rook, Christopher J. ElsonAbstract:The effect of pregnancy on the incidence and severity of Pristane-Induced Arthritis was examined along with the glycosylation status of IgG during the ante-natal and post-partum periods. It was found that Pristane-Induced Arthritis is prevented by pregnancy. In addition, the levels of agalactosyl IgG fall during pregnancy but rise to greater than normal within a few days of parturition, before resetting towards the norm shortly afterwards. Interestingly, the level of agalactosyl IgG correlates with the severity of Arthritis. As previously reported IL-6 may be an important factor, not necessarily the only one, in the production of agalactosyl IgG. Here it is clearly demonstrated that the kinetics of IL-6 activity post-pristane injection parallels the kinetics of agalactosyl IgG production. In addition, the overshoot in agalactosyl IgG levels immediately post-partum coincides with a burst in IL-6 activity. It is considered that these changes in IgG glycoform levels, or the factors which control them, may be related to the mechanisms underlying prevention/remission of Arthritis during pregnancy.
Congshan Jiang - One of the best experts on this subject based on the ideXlab platform.
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Upregulated PKM2 in Macrophages Exacerbates Experimental Arthritis via STAT1 Signaling.
Journal of Immunology, 2020Co-Authors: Jing Xu, Congshan Jiang, Manman Geng, Xipeng Wang, Yizhao Peng, Si Wang, Xiaowei Li, Fujun ZhangAbstract:Recent studies indicate that glucose metabolism is altered in rheumatoid Arthritis. We hypothesize that Pkm2, as a key regulatory enzyme of glycolysis pathway, triggers the activation of macrophages (Mφ), which results in proinflammatory cytokine production during the Arthritis progress. In this study, Pkm2 was found to be overexpressed in ED1-positive Mφ in spleens and synovial tissues from arthritic rats via immunofluorescence, Western blotting, and quantitative RT-PCR. To reveal the role of Pkm2, Dark Agouti rats were treated with either Pkm2 enzyme inhibitor shikonin or the RNA interference plasmids of Pkm2 and negative control plasmids, respectively, via i.p. injection. Pkm2 intervention could alleviate the severity of Pristane-Induced Arthritis in aspects of the macroscopic Arthritis score, perimeter changes of midpaw, and the synovitis and destruction of the bone and cartilage as well as reduce the ED1 and p-Stat1-positive cell population in rat synovial tissues. Silencing Pkm2 by RNA interference in classical activated rat and mouse Mφ resulted in less Tnf-α, Il-1β production via Stat1 signaling. Collectively, Pkm2 is highly expressed in ED1-positive Mφ of spleens and synovial tissues from arthritic rats and promotes Mφ activation via Stat1 signaling. Pkm2 might be a promising selective metabolic target molecule for rheumatoid Arthritis treatment.
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Increased expression of Th17 cytokines and interleukin-22 correlates with disease activity in Pristane-Induced Arthritis in rats.
PLOS ONE, 2017Co-Authors: Bo Wang, Congshan Jiang, Liesu Meng, Yan Zhou, Panpan Zhao, Linyu Wang, Shemin LuAbstract:: The objective of this study was to identify the key changed subtype of T helper cells (Th cells) and their cytokines in Pristane-Induced Arthritis (PIA) in rats. The severity of Arthritis was evaluated by body weight, clinical score, the perimeter of ankle and mid-paw and histological assessment of ankle joints. Cytokines of Th1, Th2 and Th17 were determined in the spleen and inguinal lymph nodes at 28 days after pristane injection by real-time qPCR. The mRNA levels of IL-22 receptors, IL-22R1 and IL-22BP, in the spleen were quantified by real-time qPCR. Additionally, IL-22 expression in synovial membrane was detected by Western blotting, and serum IL-22 concentration was determined by ELISA. Correlation between IL-22 concentration and clinical score was analyzed. By screening the cytokines of Th1, Th2 and Th17 expression profile, we found that the mRNA levels of Th17 cytokines were significantly increased in PIA rats. Particularly, a significant increase in the protein expression of IL-22 was determined in synovial membrane and serum from PIA rats, and correlated with clinical score. We conclude that IL-22 expression level was increased and correlated with disease severity, which indicated that IL-22 may play an important role in development of PIA, and was helpful to explorer the pathogenesis of rheumatoid Arthritis.
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IL‑22 expression is increased variedly in the initial phase, onset and chronic phase of a pristane‑induced Arthritis rat model
Molecular Medicine Reports, 2017Co-Authors: Bo Wang, Congshan Jiang, Liesu Meng, Yan Zhou, Ke Xu, Peng Xu, Shemin LuAbstract:: The aim of the present study was to investigate the expression pattern of T helper (Th) 17 and Th22 cell-related factors in a pristane‑induced Arthritis (PIA) rat model. PIA rats were divided into the initial phase group [day (D) 6 post‑pristane injection], the onset of clinical Arthritis group (D12), the acute Arthritis group (D26) and the chronic Arthritis group (D70). Rats injected with saline alone were used as the control group. The mRNA expression levels of interleukin (IL)‑17A, IL‑17F, interferon (IFN)‑γ, IL‑22, IL‑22 receptor (R) 1, IL‑22 binding protein (BP) and RAR‑related orphan receptor α were examined in the spleen and/or synovium of the various phases of PIA rats by reverse transcription‑quantitative polymerase chain reaction analysis. The results demonstrated that, in the spleen, IL‑22 exhibited an increasing trend in both the initial phase and the onset of disease, while the ratio of IL‑22R1/IL‑22BP increased in both phases, compared with the control group. During the acute Arthritis phase, IL‑17F and IFN‑γ were significantly increased and IL‑17A exhibited an increasing tendency in the synovium, compared with the control group. In the chronic phase, IL‑22, IL‑22R1 and IFN‑γ were increased in the spleen, while IL‑22 exhibited an increasing trend in the synovium. In addition, immunohistochemistry analysis was used to evaluate the expression of IL‑17A, IL‑21, IL‑22 and IL‑22R1 in the ankle joints of D26 PIA rats. IL‑17A was mainly expressed in infiltrated inflammatory cells in the synovium. IL‑21 and IL‑22 were both expressed in the inflammatory cells and in the articular chondrocyte of the proliferative zone. IL‑22R1 was expressed in proliferating synovial cells. In conclusion, Th17 and Th22‑related factor expression varied in different disease progression phases and in different tissues in PIA rats. IL‑22 expression exhibited an increasing trend in the initial phase and the onset phase of Arthritis and increased significantly with progression to chronic Arthritis in the PIA rat model. It is thought that IL‑22 may serve an important role in the pathological process of PIA, particularly in the chronic fluctuation phase. Therefore, it may be a candidate molecule for the treatment of rheumatoid Arthritis.
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pristane induces autophagy in macrophages promoting a stat1 irf1 tlr3 pathway and Arthritis
Clinical Immunology, 2017Co-Authors: Jing Xu, Qilan Ning, Congshan Jiang, Manman Geng, Nazim Hussain, Dongmin Li, Xiaoying Wu, Fujun Zhang, Bo Wang, Rikard HolmdahlAbstract:Abstract Autophagy is involved in both innate and adaptive immune regulation. We propose that autophagy regulates activation of TLR3 in macrophages and is thereby essential for development of Pristane-Induced Arthritis. We found that pristane treatment induced autophagy in macrophages in vitro and in vivo, in spleen cells from pristane injected rats. The induced autophagy was associated with STAT1 phosphorylation and expression of IRF1 and TLR3. Blocking the pristane activated autophagy by Wortmannin and Bafilomycin A1 or by RNAi of Becn1 led to a downregulation of the associated STAT1-IRF1-TLR3 pathway. Most importantly, the development of Arthritis was alleviated by suppressing either autophagy or TLR3. We conclude that pristane enhanced autophagy, leading to a STAT1-IRF1 controlled upregulation of TLR3 expression in macrophages, is a pathogenic mechanism in the development of Arthritis.
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pristane primed rat t cells enhance tlr3 expression of fibroblast like synoviocytes via tnf α initiated p38 mapk and nf κb pathways
Clinical Immunology, 2015Co-Authors: Congshan Jiang, Manman Geng, Xiaoying Wu, Rikard Holmdahl, Jing Xu, Liesu Meng, Shemin LuAbstract:Abstract Based on Pristane-Induced Arthritis (PIA), we found that T cells mediate TLR3 overexpression in fibroblast-like synoviocytes (FLS). The aim of this study is to determine key factors by which T cells induce TLR3 expression. Rat FLS were co-cultured with pristane primed T cell conditioned medium (PPT medium), and TLR3 expression of FLS was significantly induced. TNF-α, IFN-γ and IL-17 were dominantly expressed in PIA T cells. The overexpression of TLR3 and its related genes in FLS co-cultured with PPT medium could be reduced through blocking TNF-α pathway. CD4+ T cells from spleen of PIA rats showed increase of TNF-α secretion. P38 MAPK and NF-κB were activated in FLS by PPT medium, and their inhibitors decreased TLR3 upregulation significantly. Finally, TNF-α induced TLR3 expression was confirmed in human synovial cells. Summarily, TNF-α derived from pristane primed T cells induced TLR3 expression of FLS through activating p38 MAPK and NF-κB pathways.