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Find video protocols related to scientific articles indexed in Pubmed.
Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis.
J. Immunol.
PUBLISHED: 08-29-2014
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Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6R?, or trans signaling, mediated by soluble IL-6R? (sIL-6R?). Our study assessed the role of sIL-6R? in IPF. We demonstrated elevations of sIL-6R? in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6R?. In vivo neutralization of sIL-6R? attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6R? from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
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Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis.
PUBLISHED: 04-24-2014
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Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis.
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Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo.
J. Cell. Sci.
PUBLISHED: 04-16-2014
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Although soluble factors, such as transforming growth factor ?1 (TGF-?1), induce mesenchymal stem cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage, the role of adherens junctions in this process is not well understood. In this study, we found that cadherin-11 but not cadherin-2 was necessary for MSC differentiation into SMCs. Cadherin-11 regulated the expression of TGF-?1 and affected SMC differentiation through a pathway that was dependent on TGF-? receptor II (TGF?RII) but independent of SMAD2 or SMAD3. In addition, cadherin-11 activated the expression of serum response factor (SRF) and SMC proteins through the Rho-associated protein kinase (ROCK) pathway. Engagement of cadherin-11 increased its own expression through SRF, indicative of the presence of an autoregulatory feedback loop that committed MSCs to the SMC fate. Notably, SMC-containing tissues (such as aorta and bladder) from cadherin-11-null (Cdh11(-/-)) mice showed significantly reduced levels of SMC proteins and exhibited diminished contractility compared with controls. This is the first report implicating cadherin-11 in SMC differentiation and contractile function in vitro as well as in vivo.
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Integrins and cadherins as therapeutic targets in fibrosis.
Front Pharmacol
PUBLISHED: 01-01-2014
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Fibrosis is the excessive deposition of extracellular matrix proteins into tissues leading to scar formation, disruption of normal tissue architecture and organ failure. Despite the large clinical impact of fibrosis, treatment options are limited. Adhesion molecules, in particular ?v?6 and ?3?1 integrins and cadherin-11, have been demonstrated to be important mediators of tissue fibrosis. These data are reviewed here and provide the foundation for these molecules to be potential therapeutic targets for patients with fibrotic diseases.
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Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis.
N. Engl. J. Med.
PUBLISHED: 12-18-2013
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Background Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. Methods We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. Results Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. Conclusions Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).
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Detection and isolation of auto-reactive human antibodies from primary B cells.
Methods
PUBLISHED: 03-22-2013
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The isolation of human monoclonal antibodies (hmAb) has emerged as a versatile platform in a wide variety of contexts ranging from vaccinology to therapeutics. In particular, the presence of high titers of circulating auto-antibodies is implicated in the pathology and outcome of autoimmune diseases. Therefore, the molecular characterization of these hmAb provides an avenue to understanding the pathogenesis of autoimmune diseases. Additionally, the phenotype of the auto-reactive B cells may have direct relevance for therapeutic intervention. In this report, we describe a high-throughput single-cell assay, microengraving, for the screening, characterization and isolation of anti-citrullinated protein antibodies (ACPA) from peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis (RA) patients. Stimulated B cells are profiled at the single-cell level in a large array of sub-nanoliter nanowells (?10(5)), assessing both the phenotype of the cells and their ability to secrete cyclic-citrullinated peptide (CCP)-specific antibodies. Single B cells secreting ACPA are retrieved by automated micromanipulation, and amplification of the immunoglobulin (Ig) heavy and light chains is performed prior to recombinant expression. The methodology offers a simple, rapid and low-cost platform for isolation of auto-reactive antibodies from low numbers of input cells and can be easily adapted for isolation and characterization of auto-reactive antibodies in other autoimmune diseases.
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Biologic agents in rheumatoid arthritis: an update for managed care professionals.
J Manag Care Pharm
PUBLISHED: 11-15-2011
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Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory arthritis that clinically manifests as joint pain, stiffness, and swelling. If left untreated, persistent synovial inflammation can progress to cartilage and bone destruction and ultimately to major long-term disability and mortality. Synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, and sulfasalazine, have markedly improved clinical symptoms and slowed joint damage in RA patients. However, despite the effectiveness of synthetic DMARDs, many patients who use them continue to have clinical symptoms of inflammation and progressive joint destruction. Recent advances in our understanding of the pathogenesis of RA have led to the identification of novel cellular and molecular therapeutic targets. Biologic agents aimed at these targets have provided some evidence of effectiveness that is transforming the management of RA.
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Assessment of disease activity and treatment outcomes in rheumatoid arthritis.
J Manag Care Pharm
PUBLISHED: 11-15-2011
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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which primarily causes a symmetric polyarthritis. Clinical manifestations of the disease include joint pain, stiffness, and swelling. Unless treated, this debilitating disease can progress into long-term disability. Medications for RA include synthetic disease-modifying antirheumatic drugs (DMARDs) and biologic agents. The rapid expansion of new RA drugs into the market has led to a need for health care practitioners to understand the effectiveness of each medication and the indications of use including when to initiate and stop therapies. Clinical assessment tools, including biomarkers used to indicate RA and the progression of the disease, have been proven effective for making a diagnosis and determining effective treatment regimens. Disease activity scales are also useful for guiding diagnoses and monitoring patients to assess treatment effectiveness.
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Core management principles in rheumatoid arthritis to help guide managed care professionals.
J Manag Care Pharm
PUBLISHED: 11-15-2011
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Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that affects approximately 1% of the population. Initial symptoms include joint swelling, stiffness, and tenderness, which are all causes of disability. The diagnosis of RA is based on patient history of joint pain and stiffness, the documentation of symmetric polyarticular joint synovitis, and laboratory measures including radiographs, inflammatory markers, and autoantibodies. As the disease progresses, synovial inflammation leads to cartilage damage, bone erosions, and joint destruction, the major causes of long-term disability. RA is associated with many comorbidities and complications, including cardiovascular disease, which is responsible for higher rates of mortality among patients compared with the general population. Over the past 2 decades, advances in the development of synthetic disease-modifying antirheumatic drugs (DMARDs) and biologic agents for RA have markedly changed treatment goals and management strategies.
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A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.
Hum. Mol. Genet.
PUBLISHED: 11-10-2011
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A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(?2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
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Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-? production and epithelial to mesenchymal transition.
FASEB J.
PUBLISHED: 10-11-2011
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Pulmonary fibrosis, characterized by excess deposition of extracellular matrix by myofibroblasts, is a serious component of chronic lung diseases. Cadherin-11 (CDH11) is increased in wound healing and fibrotic skin. We hypothesized that CDH11 is increased in pulmonary fibrosis and contributes its development. CDH11 expression was assessed in lung tissue from idiopathic pulmonary fibrosis patients. The role of CDH11 in lung fibrosis was determined using the bleomycin model of pulmonary fibrosis, and in vitro analyses were performed on A549 cells during the process of epithelial to mesenchymal transition (EMT). Immunohistochemical studies demonstrated CDH11 expression on fibroblasts, epithelial cells, and alveolar macrophages of patients with pulmonary fibrosis and mice given bleomycin. Interestingly, CDH11-deficient mice had decreased fibrotic endpoints in the bleomycin model of pulmonary fibrosis compared to wild-type mice. Furthermore, anti-CDH11-neutralizing monoclonal antibodies successfully treated established pulmonary fibrosis induced by bleomycin. TGF-? levels were reduced in bronchoalveolar lavage (BAL) fluid, BAL cells, and primary alveolar macrophages from CDH11-deficient mice. Mechanistic studies demonstrated that TGF-? up-regulated CDH11 expression on A549 cells, and inhibition of CDH11 expression using siRNA reduced TGF-?-induced EMT. Together, these results identify CDH11 as a novel therapeutic target for pulmonary fibrosis.
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Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 09-16-2011
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Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.
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Targeting STAT4 in systemic sclerosis: a promising new direction.
Expert Rev Clin Immunol
PUBLISHED: 07-28-2011
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Evaluation of: Avouac J, Fürnrohr BG, Tomcik M et al. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum. 63(3), 800-809 (2011). STAT4 has been identified as a genetic risk factor for the development of autoimmune diseases including systemic sclerosis. STAT4 regulates Th1 cell development and cell-mediated immunity, but it is not known how it may regulate the development of dermal fibrosis. Using the bleomycin-induced dermal fibrosis model, it has now been demonstrated that STAT4-deficient mice have reduced dermal fibrosis in part via STAT4-dependent alterations in T-cell proliferation and cytokine production. These data stress the importance of STAT4 in autoimmune diseases such as systemic sclerosis and provide an important direction for future research to improve our understanding of systemic sclerosis pathogenesis.
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Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
PLoS Genet.
PUBLISHED: 05-25-2011
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The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P?=?2.32×10(-12), OR?=?0.75). Also, rs12540874 in GRB10 gene (P?=?1.27 × 10(-6), OR?=?1.15) and rs11047102 in SOX5 gene (P?=?1.39×10(-7), OR?=?1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P?=?1.79×10(-61), OR?=?2.48), in the HLA-DPA1/B1 loci with ATA (P?=?4.57×10(-76), OR?=?8.84), and in NOTCH4 with ACA P?=?8.84×10(-21), OR?=?0.55) and ATA (P?=?1.14×10(-8), OR?=?0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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Stress and autoimmunity.
Immunol Allergy Clin North Am
PUBLISHED: 05-25-2011
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Stress reduction interventions can have a positive therapeutic effect in autoimmune disease patients. Physicians and patients must recognize the potential for stress to impact autoimmune diseases and how stress management should be considered in a multidimensional treatment approach. This article evaluates the effects of stress as a trigger and a modulator, and stress reduction as a treatment option in rheumatoid arthritis.
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Anti-fibrillarin antibody in African American patients with systemic sclerosis: immunogenetics, clinical features, and survival analysis.
J. Rheumatol.
PUBLISHED: 05-15-2011
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Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
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Association study of ITGAM, ITGAX, and CD58 autoimmune risk loci in systemic sclerosis: results from 2 large European Caucasian cohorts.
J. Rheumatol.
PUBLISHED: 03-01-2011
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Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.
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Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts.
Arthritis Res. Ther.
PUBLISHED: 01-11-2011
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Increased levels of genes in the type I interferon (IFN) pathway have been observed in patients with systemic sclerosis (SSc), or scleroderma. How type I IFN regulates the dermal fibroblast and its participation in the development of dermal fibrosis is not known. We hypothesized that one mechanism by which type I IFN may contribute to dermal fibrosis is through upregulation of specific Toll-like receptors (TLRs) on dermal fibroblasts. Therefore, we investigated the regulation of TLR expression on dermal fibroblasts by IFN.
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Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5.
J. Rheumatol.
PUBLISHED: 10-15-2010
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to identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.
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The genetics of systemic sclerosis.
Discov Med
PUBLISHED: 09-03-2010
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Systemic sclerosis (SSc, scleroderma) is an autoimmune disease clinically characterized by progressive fibrosis in the skin and internal organs. While the pathogenesis of SSc is not completely understood, familial studies and genetic studies suggest that SSc is a complex polygenic disease. In the current review, we will discuss recent studies investigating genetic susceptibility to SSc. Candidate gene studies have identified critical immunoregulatory genes and gene regions including BANK1, FAM167A-BLK, IL23R, IRF5, STAT4, TBX21, and TNFSF4 as susceptibility genes for the development of SSc. More recently a genome-wide association study has been performed and identified CD247 (CD3-zeta) as a novel genetic risk factor for the susceptibility to SSc. Together these genetic association studies have substantially advanced our understanding of SSc pathogenesis and form the foundation for future studies seeking to understand the complexities of SSc.
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Gene expression changes in multiple sclerosis relapse suggest activation of T and non-T cells.
Mol. Med.
PUBLISHED: 06-01-2010
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A defining feature of multiple sclerosis (MS) is the occurrence of clinical relapses separated by periods of clinical stability. Better understanding of the events underlying clinical relapse might suggest new approaches to treatment. The objective of this study was to measure changes in the expression of RNA in the blood during relapse. We used microarrays to measure mRNA expression in paired samples from 14 MS patients during clinical relapse and while stable. Seventy-one transcripts changed expression at the P < 0.001 significance level. The most notable finding was decreased expression of transcripts with regulatory function, expressed primarily in non-T cells. These decreased transcripts included the interleukin-1 receptor antagonist, which had a corresponding decrease in the protein concentration in serum. Transcripts with increased expression were expressed primarily in T cells. Pathways analysis suggested involvement of the cytokine network, coagulation and complement cascades, IL-10 signaling and NF-?B signaling. We conclude that there are alterations of mRNA expression in both T cells and non-T cells during MS relapse.
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Case of a misplaced IVC filter: a lesson to learn.
Cardiovasc Intervent Radiol
PUBLISHED: 02-27-2010
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The inferior vena cava (IVC) filter insertion is a well established procedure to prevent significant pulmonary embolism in selected situations. It is generally considered straight forward without significant complications. We report an interesting case of a young postpartum woman in whom an IVC filter was misplaced in the right gonadal vein. This complication is only rarely reported. Presence of prominent right gonadal vein must always be kept in mind during trans-jugular placement of infra renal filter in the IVC in post partum women.
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Endovascular treatment for peripheral pulmonary artery aneurysm.
Vascular
PUBLISHED: 02-04-2010
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A 42-year-old male presented with recurrent hemoptysis owing to a leaking peripheral pulmonary artery aneurysm. He was treated with selective coil embolization of the right posterior basal segmental artery to achieve hemostasis. This case is reported for its unsuspected presentation and rarity and to highlight the use of catheter coil embolization to achieve endovascular exclusion of the aneurysm from pulmonary circulation.
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Systemic sclerosis and lupus: points in an interferon-mediated continuum.
Arthritis Rheum.
PUBLISHED: 01-30-2010
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To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE).
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The genetics of scleroderma (systemic sclerosis).
Curr Opin Rheumatol
PUBLISHED: 01-22-2010
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To determine the advances made in the genetics of scleroderma in candidate gene association studies.
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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.
Nat. Genet.
PUBLISHED: 01-04-2010
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.
Arthritis Rheum.
PUBLISHED: 12-02-2009
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility.
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Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.
J. Rheumatol.
PUBLISHED: 11-16-2009
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IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
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Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.
Ann. Rheum. Dis.
PUBLISHED: 09-23-2009
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It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
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Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls.
Ann. Rheum. Dis.
PUBLISHED: 07-12-2009
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To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case-control association study.
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Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.
J. Autoimmun.
PUBLISHED: 07-07-2009
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Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.
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Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations.
Arthritis Res. Ther.
PUBLISHED: 06-08-2009
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Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets.
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IRF5 polymorphism predicts prognosis in patients with systemic sclerosis.
Ann. Rheum. Dis.
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The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.
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Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis.
J. Rheumatol.
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Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.
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Osteopontin in systemic sclerosis and its role in dermal fibrosis.
J. Invest. Dermatol.
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Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Here, we determined whether OPN levels are increased in a large cohort of patients with systemic sclerosis (SSc) and whether OPN contributes to the development of dermal fibrosis. The plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared with healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin (bleo)-induced dermal fibrosis model. OPN-deficient (OPN(-/-)) mice developed less dermal fibrosis compared with wild-type (WT) mice in the bleo-induced dermal fibrosis model. Additional in vivo studies have demonstrated that lesional skin from OPN(-/-)mice had fewer Mac-3-positive cells, fewer myofibroblasts, decreased transforming growth factor (TGF)-? and genes in the TGF-? pathway, and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and extracellular signal-regulated kinase. In vitro, OPN(-/-) dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGF-?. Finally, TGF-? production by OPN-deficient macrophages was reduced compared with WT. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that it may be a new therapeutic target in SSc.
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