bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct topography of erosion and new bone formation in achilles tendon enthesitis: Implications for understanding the link between inflammation and bone formation in spondylarthritis
Authors: McGonagle Dennis , Wakefield Richard J. , Tan Ai Lyn , D'Agostino Maria Antonietta , Toumi Hechmi , Hayashi Koji , Emery Paul , Benjamin Michael 
Published: August 2008

AbstractObjectiveThis study combined ultrasonography of the Achilles tendon enthesis at different stages of spondylarthritis (SpA) with microanatomic studies of normal cadaveric entheses, with the aim of exploring the relationship between bone erosion and new bone formation in enthesitis.MethodsThirty‐seven patients with SpA and Achilles tendon enthesitis (20 with early SpA and 17 with chronic SpA) and 10 normal control subjects underwent ultrasound scanning. The presence of bone erosion and spur formation was recorded at 3 sites: the proximal and distal halves of the enthesis and the adjacent calcaneal superior tuberosity. Parallel histologic analysis was performed on cadaveric Achilles tendon entheses to determine whether regional variations in bone density and trabecular architecture in relation to fibrocartilage distribution are related to disease patterns.ResultsBone erosion in patients with early SpA occurred at either the proximal insertion or the superior tuberosity (11 of 20 patients; P < 0.001 versus distal enthesis). Very small spurs, which were present almost exclusively at the distal enthesis, were evident in patients with early SpA and in normal control subjects. However, large spurs were evident distally only in patients with chronic SpA (9 of 17 patients, compared with none of 20 patients with early SpA; P < 0.0001). Histologic studies showed that aged normal individuals had small spurs at the corresponding location. The bone‐to‐marrow ratio was also significantly lower in the regions prone to erosions (P < 0.05).ConclusionBone erosion in association with Achilles tendon enthesitis in SpA is anatomically uncoupled from bone formation—the 2 processes are topographically and temporally distinct. We thus conclude that disease patterns in SpA are related to normal enthesis structure and biomechanics.
Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis
Authors: López‐Pedrera Chary , Cuadrado Maria José , Herández Vanessa , Buendïa Paula , Aguirre Maria Angeles , Barbarroja Nuria , Torres Luis Arïstides , Villalba José Manuel , Velasco Francisco , Khamashta Munther 
Published: August 2008

AbstractObjectiveAntiphospholipid antibodies (aPL) are closely related to the development of thrombosis, but the exact mechanism(s) leading to thrombotic events remains unknown. In this study, using proteomic techniques, we evaluated changes in protein expression of monocytes from patients with antiphospholipid syndrome (APS) related to the pathophysiology of the syndrome.MethodsFifty‐one APS patients were included. They were divided into 2 groups: patients with previous thrombosis, and patients with recurrent spontaneous abortion. As controls, we studied patients with thrombosis but without aPL, and age‐ and sex‐matched healthy subjects.ResultsThe proteins that were more significantly altered among monocytes from APS patients with thrombosis (annexin I, annexin II, protein disulfide isomerase, Nedd8, RhoA proteins, and Hsp60) were functionally related to the induction of a procoagulant state as well as to autoimmune‐related responses. Proteins reported to be connected to recurrent spontaneous abortion (e.g., fibrinogen and hemoglobin) were also determined to be significantly deregulated in APS patients without thrombosis. In vitro treatment with IgG fractions purified from the plasma of APS patients with thrombosis changed the pattern of protein expression of normal monocytes in the same way that was observed in vivo for monocytes from APS patients with thrombosis.ConclusionFor the first time, proteomic analysis has identified novel proteins that may be involved in the pathogenic mechanisms of APS, thus providing potential new targets for pathogenesis‐based therapies for the disease.
Vav/Phospholipase Cγ2–mediated control of a neutrophil‐dependent murine model of rheumatoid arthritis
Authors: Cremasco Viviana , Graham Daniel B. , Novack Deborah V. , Swat Wojciech , Faccio Roberta 
Published: August 2008

AbstractObjectiveAccumulating evidence indicates an important role of neutrophils in the development of rheumatoid arthritis (RA). Recruitment of neutrophils to the joint space and release of proteolytic enzymes can exacerbate tissue damage and the inflammatory response related to RA. Engagement of β2 integrin and subsequent activation of downstream signaling have been shown to be fundamental for activation of neutrophil effector functions. The aim of this study was to test the hypothesis that Vav and phospholipase Cγ2 (PLCγ2), two molecules involved in integrin signaling, are required for arthritis generation and neutrophil activation in a mouse model of arthritis.MethodsArthritis was induced in wild‐type (WT), Vavnull, and PLCγ2−/− mice using the K/BxN serum–transfer model. Neutrophil function was assessed by analyses of adhesion, spreading, and degranulation on integrin‐dependent substrates. Regulation of integrin signaling was determined by analyzing the phosphorylation of Pyk‐2, Src, and ERK.ResultsVavnull and PLCγ2−/− mice were protected from inflammation and bone erosion in the K/BxN serum–transfer model of arthritis. Mechanistically, Vav and PLCγ2 control neutrophils mediated spreading and degranulation on integrin‐dependent substrates. Consequently, the Vav/PLCγ2 axis, acting downstream of the integrin receptor, modulated the activation of Pyk‐2, Src, and ERK.ConclusionOur findings show that Vav cooperates with PLCγ2 in modulating neutrophil activation downstream of the integrin receptor. This study identifies a Vav/PLCγ2‐dependent signaling pathway as a possible therapeutic target for the treatment of inflammation and bone disruption in arthritis.
Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis
Authors: Nile Christoper J. , Read Robert C. , Akil Mohammed , Duff Gordon W. , Wilson Anthony G. 
Published: August 2008

AbstractObjectiveGenetic variation in the gene for interleukin‐6 (IL‐6) contributes to the pathogenesis of inflammatory arthritis, but the role, if any, of epigenetic variability has not been reported. The aims of this study were to compare the DNA methylation status of the IL6 promoter in rheumatoid arthritis (RA) patients and control subjects and to study the effects on gene expression.MethodsGenomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) obtained from RA patients and healthy controls. Macrophages from healthy controls were isolated and stimulated with lipopolysaccharide (LPS). Methylation status was determined using bisulfite genomic sequencing and IL6 messenger RNA (mRNA) levels by quantitative polymerase chain reaction. Gel shift assays were performed with methylated or unmethylated probes and HeLa cell nuclear extract.ResultsThe proximal CpG motifs (–666 to +27) were predominantly unmethylated and the upstream motifs (–1099 to –1001) were highly methylated in PBMCs from patients and controls. Methylation of individual CpG motifs was similar, except at –1099C, which was less methylated in the patients than in the controls (58% versus 98%; P = 1 × 10−6). To test whether this observation might relate to gene regulation, LPS‐stimulated macrophages were grouped according to their IL6 mRNA stimulation index (SI). The level of methylation at –1099C was significantly lower in the group with high (SI >75) compared with the group with low (SI <10) induced mRNA levels (71% versus 93%; P = 0.007). Gel shift assays revealed decreased protein binding to the –1099C unmethylated probe.ConclusionThese data suggest that methylation of a single CpG in the IL6 promoter region may affect IL6 gene regulation and may play a role in the pathogenesis of RA.
Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis
Authors: Landau Dan‐Avi , Rosenzwajg Michelle , Saadoun David , Trébeden‐Negre Hélène , Klatzmann David , Cacoub Patrice 
Published: August 2008

AbstractObjectiveMixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells. The aim of this study was to prospectively evaluate the evolution of this defect during the course of antiviral treatment.MethodsTreg cell frequencies and numbers were analyzed in 131 patients with chronic HCV infection (including 66 with MC vasculitis) and 20 healthy volunteer donors. Measurements were taken before, during, and after treatment with PEGylated interferon alfa‐2b plus ribavirin.ResultsAt baseline, patients with MC vasculitis had a significantly lower frequency and number of Treg cells than did patients without MC vasculitis. Complete remission of MC vasculitis following antiviral treatment was associated with a significant increase in Treg cell levels compared with baseline. In contrast, Treg cell levels in nonresponders or partial responders, which did not differ from those in complete responders at baseline, remained unchanged over the course of the study.ConclusionThe strong positive correlation between clinical responses and Treg cell levels provides further support for the central role of Treg cells in the pathogenesis of HCV‐induced MC vasculitis and emphasizes the dual role of Treg cells in chronic HCV infection: while Treg cells may hinder viral elimination, they also limit autoimmune injury.
Natural killer cell degeneration exacerbates experimental arthritis in mice via enhanced interleukin‐17 production
Authors: Lo Cherry Kam Chun , Lam Queenie Lai Kwan , Sun Lingyun , Wang Shengjun , Ko King‐Hung , Xu Huaxi , Wu Chang‐You , Zheng Bo‐Jian , Lu Liwei 
Published: August 2008

AbstractObjectiveAn altered phenotype and dysfunction of natural killer (NK) cells have been observed in patients with rheumatoid arthritis. The aim of this study was to determine whether dysregulated NK cells contribute to the pathogenesis of experimental arthritis.MethodsFor initiation of collagen‐induced arthritis (CIA), DBA/1J mice were immunized with type II collagen in Freund's adjuvant. Control mice were immunized with adjuvant alone. NK cells from the blood, spleens, and bone marrow of immunized mice were analyzed by flow cytometry. Levels of interleukin‐17 (IL‐17) secretion and autoantibody production were measured by enzyme‐linked immunosorbent assays. Immunized mice in which NK cells were depleted by anti–asialo GM1antibody treatment were assessed for the development of CIA. Moreover, sorting‐purified NK cells from both mice with CIA and control mice were analyzed for cytokine gene expression.ResultsWe observed markedly reduced frequencies of NK cells in the blood and spleens of mice with CIA compared with the frequencies in adjuvant‐treated control mice. Upon NK cell depletion, immunized mice displayed an early onset of arthritis with more severe clinical symptoms, which correlated with increased plasma cell generation and autoantibody production. Moreover, a substantially increased number of IL‐17–secreting cells in synovial tissue and more pronounced joint damage were observed. Freshly isolated NK cells from mice with CIA showed markedly reduced expression of interferon‐γ (IFNγ). Furthermore, coculture of normal NK cells and CD4+ T cells revealed that NK cells strongly suppressed production of Th17 cells via their IFNγ production.ConclusionThese results suggest that NK cells play a protective role in the development of experimental arthritis, an effect that is possibly mediated by suppressing Th17 cell generation via IFNγ production.
Prevention of murine antiphospholipid syndrome by BAFF blockade
Authors: Kahn Philip , Ramanujam Meera , Bethunaickan Ramalingam , Huang Weiqing , Tao Haiou , Madaio Michael P. , Factor Stephen M. , Davidson Anne 
Published: August 2008

AbstractObjectiveThis study was undertaken to determine whether BAFF blockade can be used to prevent or treat antiphospholipid syndrome in a mouse model.MethodsEight‐ and 12‐week‐old (NZW × BXSB)F1 mice were treated with BAFF‐R‐Ig or TACI‐Ig alone or in addition to a short course of CTLA‐4Ig. Mice were monitored for thrombocytopenia and proteinuria. Sera were tested for anticardiolipin antibodies (aCL), BAFF levels, and levels of soluble vascular cell adhesion molecule and E‐selectin. Mice were killed at 17, 22, or 32 weeks of age, and kidneys and hearts were subjected to histologic examination. Spleen cells were phenotyped and enzyme‐linked immunospot assays for autoantibody‐producing B cells were performed.ResultsBoth BAFF‐R‐Ig and TACI‐Ig prevented disease onset and significantly prolonged survival. Treated mice had significantly smaller spleens than controls, with fewer B cells and fewer activated and memory T cells. BAFF blockade did not prevent the development of aCL, and there was only a modest delay in the development of thrombocytopenia. However, treated mice had significantly less nephritis and myocardial infarcts than did controls.ConclusionOur findings suggest that aCL are generated in the germinal center, which is relatively independent of BAFF. Effector function of antiplatelet antibodies was only modestly affected by BAFF blockade. In contrast, myocardial infarctions were prevented, suggesting that triggering of thromboses requires both autoantibodies and mediators of inflammation. Similarly, renal damage requires both immune complexes and effector cells. The dissociation between autoantibody production and inflammation that may occur with B cell–depleting therapies underscores the role of B cells as effector cells in the autoimmune response.
Association of body fat with C‐reactive protein in rheumatoid arthritis
Authors: Giles Jon T. , Bartlett Susan J. , Andersen Ross , Thompson Richard , Fontaine Kevin R. , Bathon Joan M. 
Published: August 2008

AbstractObjectiveThe serum C‐reactive protein (CRP) concentration is commonly used in rheumatoid arthritis (RA) as a surrogate marker of systemic inflammation, presumably induced by synovitis. However, other tissues, such as adipose tissue, can induce CRP production. This study was undertaken to explore the associations between measures of adiposity and CRP levels in RA.MethodsOne hundred ninety‐six men and women with RA underwent anthropometric assessment and total body dual‐energy x‐ray absorptiometry for measurement of total and regional body fat and lean mass. The associations between measures of fat and lean mass and serum levels of CRP and interleukin‐6 (IL‐6) were determined in analyses stratified by sex, with adjustment for pertinent demographic, lifestyle, and RA disease and treatment covariates as well as for the potential modifying effects of articular activity and biologic pharmacotherapeutic agents.ResultsAll measures of adiposity were significantly associated with the level of CRP in women, but not in men. In women, the measure of adiposity that showed the strongest association with the CRP level was truncal fat, in which, in adjusted analyses, each kilogram increase was associated with a 0.101‐unit increase in the logarithmically transformed CRP level (P < 0.001). Neither the level of articular activity nor the use of biologic agents significantly modified this association in women. However, in men, elevated articular involvement was associated with a decreasing CRP level as truncal fat increased. For all analyses, substitution of IL‐6 for CRP produced similar findings.ConclusionAdiposity is independently associated with CRP levels in women with RA, and thus may confound the estimation of RA disease activity when serum CRP concentration is used as a surrogate for systemic inflammation.
Decreased expression of caveolin 1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis
Authors: Galdo Francesco Del , Sotgia Federica , de Almeida Cecilia J. , Jasmin Jean‐Francois , Musick Megan , Lisanti Michael P. , Jiménez Sergio A. 
Published: August 2008

AbstractObjectiveRecent studies have implicated caveolin 1 in the regulation of transforming growth factor β (TGFβ) downstream signaling. Given the crucial role of TGFβ in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.MethodsCAV1 expression in tissues was analyzed by immunofluorescence and confocal microscopy. The extent of tissue fibrosis in Cav1‐knockout mice was assessed by histologic/histochemical analyses and quantified by hydroxyproline assays. Cav1‐null and SSc fibroblast phenotypes and protein production were analyzed by real‐time polymerase chain reaction, immunofluorescence, Western blot, and multiplexed enzyme‐linked immunosorbent assay techniques. The effects of restoration of caveolin 1 function in SSc fibroblasts in vitro were also examined using a cell‐permeable recombinant CAV1 peptide.ResultsCAV1 was markedly decreased in the affected lungs and skin of SSc patients. Cav1‐knockout mice developed pulmonary and skin fibrosis. Down‐regulation of caveolin 1 was maintained in cultured SSc fibroblasts, and restoration of caveolin 1 function in vitro normalized their phenotype and abrogated TGFβ stimulation through inhibition of Smad3 activation.ConclusionCaveolin 1 appears to participate in the pathogenesis of tissue fibrosis in SSc. Restoration of caveolin 1 function by treatment with a cell‐permeable peptide corresponding to the CAV1 scaffolding domain may be a novel therapeutic approach in SSc.
Association of the STAT4 gene with increased susceptibility for some immune‐mediated diseases
Authors: Martínez A. , Varadé J. , Márquez A. , Cénit M. C. , Espino L. , Perdigones N. , Santiago J. L. , Fernández‐Arquero M. , de la Calle H. , Arroyo R. , Mendoza J. L. , Fernández‐Gutiérrez B. , de la Concha E. G. , Urcelay E. 
Published: August 2008

AbstractObjectiveThe STAT4 gene encodes a transcription factor involved in the signaling pathways of several cytokines, including interleukin‐12 (IL‐12), the type I interferons, and IL‐23. Recently, the association of a STAT4 haplotype marked by rs7574865 with rheumatoid arthritis (RA) and systemic lupus erythematosus was reported. The aim of this study was to investigate the role of this STAT4 tagging polymorphism in other immune‐mediated diseases.MethodsThe study group comprised 2,776 consecutively recruited Spanish individuals: 575 with RA, 440 with multiple sclerosis, 700 with inflammatory bowel disease, 311 with type 1 diabetes, and 723 ethnically matched healthy control subjects. The STAT4 polymorphism rs7574865 was genotyped using a predesigned TaqMan assay. Allele and genotype frequencies in patients and control subjects were compared by chi‐square test.ResultsThe association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 × 10−6, odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31–1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07–1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07–1.71). In contrast, the genotypic distribution of this polymorphism showed no difference between patients with multiple sclerosis and healthy control subjects (for T versus G, P = 0.83, OR 1.02, 95% CI 0.82–1.28).ConclusionThe STAT4 gene is emerging as a novel common risk factor for diverse complex diseases.
Replication of the tumor necrosis factor receptor−associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family‐based study
Authors: Kurreeman F. A. S. , Rocha D. , Houwing‐Duistermaat J. , Vrijmoet S. , Teixeira V. H. , Migliorini P. , Balsa A. , Westhovens R. , Barrera P. , Alves H. , Vaz C. , Fernandes M. , Pascual‐Salcedo D. , Michou L. , Bombardieri S. , Radstake T. , van Riel P. , van de Putte L. , Lopes‐Vaz A. , Prum B. , Bardin T. , Gut I. , Cornelis F. , Huizinga T. W. J. , Petit‐Teixeira E. , Toes R. E. M. ,   European Consortium on Rheumatoid Arthritis Families
Published: August 2008

AbstractObjectiveWe recently showed, using a candidate gene approach in a case–control association study, that a 65‐kb block encompassing tumor necrosis factor receptor−associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case–control association studies, family‐based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family‐based approach.MethodsA total of 1,356 western European white individuals from 452 “trio” families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay.ResultsWe observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2‐fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04–1.50).ConclusionUsing a family‐based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.