bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coordinate expression of activating Fcγ receptors I and III and inhibiting Fcγ receptor type II in the determination of joint inflammation and cartilage destruction during immune complex–mediated arthritis
Authors: Nabbe K. C. A. M. , Blom A. B. , Holthuysen A. E. M. , Boross P. , Roth J. , Verbeek S. , Van Lent P. L. E. M. , Van Den Berg W. B. 
Published: January 2003

AbstractObjectiveTo study the role of the activating Fcγ receptor types I and III (FcγRI and FcγRIII, respectively) and the inhibiting Fcγ receptor II (FcγRII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes.MethodsImmune complex–mediated arthritis (ICA) was passively induced by lysozyme–antilysozyme complexes in FcγRI‐, FcγRIII‐, and FcγRII‐knockout mice and their wild‐type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]–mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid‐related proteins 8 and 14 (MRP8 and MRP14, respectively).ResultsInflux and activation of inflammatory cells (MRP expression) during ICA was decreased in FcγRIII‐deficient mice and enhanced in mice lacking FcγRII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking FcγRIII showed almost no PG depletion, whereas in FcγRII−/− mice, PG depletion was increased 3–7‐fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP‐mediated VDIPEN expression, was reduced in FcγRIII−/− and FcγRI−/− mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in FcγRII−/− mice. In FcγRI−/− and FcγRIII−/− mice, VDIPEN expression was 90–99% lower, whereas in FcγRII−/− mice, VDIPEN expression was increased 4‐fold. Chondrocyte death was reduced in FcγRIII−/− mice (68% lower) and enhanced in FcγRII−/− mice (6–12‐fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in FcγRII−/− arthritic joints.ConclusionDuring ICA, FcγRIII is the dominant activating receptor mediating joint inflammation, whereas both FcγRI and FcγRIII are involved in cartilage destruction. FcγRII inhibits both joint inflammation and severe cartilage destruction during ICA.
Induction of aggrecanase 1 (ADAM‐TS4) by interleukin‐1 occurs through activation of constitutively produced protein
Authors: Pratta Michael A. , Scherle Peggy A. , Yang Gengjie , Liu Rui‐Qin , Newton Robert C. 
Published: January 2003

AbstractObjectiveTo study the production of aggrecanase 1 (ADAM‐TS4) in monolayer chondrocytes, capsular fibroblasts, and cartilage.MethodsBovine nasal and articular cartilage, monolayer chondrocytes, and capsular fibroblasts were incubated in the absence and presence of interleukin‐1 (IL‐1). ADAM‐TS4 production was evaluated by immunofluorescence or by Western blot analysis. Aggrecanase activity was measured in cells grown on an immobilized peptide substrate, and peptide cleavage was monitored by enzyme‐linked immunosorbent assay.ResultsThere was constitutive production of ADAM‐TS4 in both cells and tissue. The protein was associated with the extracellular matrix based on the observation that the staining could be reduced following treatment of chondrocytes with heparin or exposure to chondroitinase ABC. Interestingly, there was no detectable change in the abundance of ADAM‐TS4 in response to IL‐1. Western blot analysis of cell lysates from IL‐1–stimulated chondrocytes showed no evidence of increased ADAM‐TS4 production, but resulted in activation of ADAM‐TS4. The activation was associated with an increased generation in the aggrecanase neoepitope NITEGE in nasal cartilage in response to IL‐1. These data suggest that induction of aggrecanase activity both in cells and in cartilage by IL‐1 may involve the stimulation of an activator of ADAM‐TS4. Consistent with this observation, culture of chondrocytes on a solid support containing a peptide substrate resulted in the generation of aggrecanase‐mediated cleavage that could be blocked by selective inhibitors of ADAM‐TS4.ConclusionThese data support the hypothesis that ADAM‐TS4 is constitutively produced in these cells and tissue, and that stimulation by IL‐1 results in aggrecanase activation. Thus, the activator could be a potential target by which to control aggrecanase‐mediated degradation in arthritic diseases.
Influence of disease‐modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: Results from a large observational inception study
Authors: Bukhari M. A. S. , Wiles N. J. , Lunt M. , Harrison B. J. , Scott D. G. I. , Symmons D. P. M. , Silman A. J. 
Published: January 2003

AbstractObjectiveTo determine the effect of early treatment with disease‐modifying antirheumatic drugs (DMARDs) in reducing radiographic progression over a 5‐year period in patients with new‐onset inflammatory polyarthritis.MethodsThree hundred thirty‐five consecutive patients with paired radiographs obtained 1 year and 5 years after enrollment in a population‐based arthritis register were studied. Logistic regression was used to model differences in baseline factors associated with the start of DMARDs. The time from symptom onset to first use of DMARDs was stratified to represent 4 groups: no DMARD use, <6 months, 6–12 months, and >12 months. Radiographs of the hands and feet were scored using the Larsen method. Progression in the Larsen score was evaluated as a 5‐year score adjusted for the first film score. Negative binomial regression was used to compare Larsen score progression for each of the 3 treatment groups with that for patients not receiving DMARDs. Results were then adjusted for severity, based on propensity modeling.ResultsPatients who received treatment had more radiographic progression than did patients who were untreated. Coefficients (95% confidence intervals), expressed as a multiple of the Larsen score in DMARD‐treated patients compared with untreated patients, were as follows: 1.6 (1.1–2.3) for <6 months, 2.4 (1.5–3.6) for 6–12 months, and 2.0 (1.4–2.8) for >12 months. As expected, patients receiving treatment had more severe disease at baseline. Using the propensity score as a method of adjusting for disease severity, the influence of treatment on outcome became attenuated as follows: 1.1 (0.8–1.7) for <6 months, 1.6 (1.0–2.6) for 6–12 months, and 1.5 (1.0–2.2) for >12 months. This effect was also seen in the crude Larsen score at year 5.ConclusionIn this observational study, DMARD treatment was a marker not only of worse disease at presentation but also of the radiographic state and radiographic progression at 5 years. After adjustments were made for baseline disease severity, earlier therapy was shown to have a beneficial effect on outcome.
Human scleroderma sera contain autoantibodies to protein components specific to the U3 small nucleolar RNP complex
Authors: Yang Jian‐Ming , Hildebrandt Bernhard , Luderschmidt Christoph , Pollard K. Michael 
Published: January 2003

AbstractObjectiveTo determine whether antifibrillarin autoantibodies in scleroderma patients are associated with autoantibodies to protein components specific for U3 small nucleolar RNP (U3 snoRNP).MethodsSera from 220 scleroderma patients were examined for antinucleolar autoantibodies (ANoA) and for antibodies to fibrillarin and the U3 snoRNP–specific proteins Mpp10 and hU3‐55K. Clinical correlates were determined for the different autoantibody specificities.ResultsFifty‐nine of the 220 patients were positive for ANoA, and 31 of these patients were antifibrillarin positive. Anti–hU3‐55K was found in 10 patients, all of whom were antifibrillarin positive. Twenty‐nine patients had anti‐Mpp10 antibodies; 23 of these were antifibrillarin positive and 6 were antifibrillarin negative. ANoA, including antifibrillarin, anti–hU3‐55K, and anti‐Mpp10, were associated with diffuse, rather than limited, systemic or localized scleroderma. Esophageal and lung involvement were more common in patients with antifibrillarin and anti‐Mpp10 antibodies, and the highest frequency was in patients with anti‐Mpp10 alone.ConclusionAntifibrillarin autoantibodies are associated with autoantibodies to protein components specific to U3 snoRNP, particularly Mpp10. The prevalence of anti‐Mpp10 antibodies in antifibrillarin‐positive patients suggests that the U3 snoRNP particle is a source of immunogenic/antigenic material for the anti‐snoRNP response in scleroderma. Autoantibodies to snoRNP components were more frequent in patients with diffuse scleroderma than in those with either the limited systemic or localized forms. The increased expression of these antibodies in patients with the more severe form of scleroderma, coupled with the observations that fibrillarin expression is positively linked to collagen expression in fibroblasts and that fibrillarin is overexpressed in scleroderma fibroblasts, suggests a source of snoRNP to initiate and maintain these autoantibody responses.
Identification of an IL1A gene segment that determines aberrant constitutive expression of interleukin‐1α in systemic sclerosis
Authors: Kawaguchi Yasushi , Hara Masako , Kamatani Naoyuki , Wright Timothy M. 
Published: January 2003

AbstractObjectiveTo further explore the mechanisms of transcriptional regulation of the IL1A gene in fibroblasts from the affected skin of patients with systemic sclerosis (SSc).MethodsThe transcription activity of IL1A was estimated by nuclear run‐on assay. A reporter construct (pLuc.–1437) was prepared that contained a 1.5‐kb genomic fragment extending from −1437 to +39 relative to the transcription start site of the IL1A gene inserted upstream of the luciferase gene. The DNA protein binding activity for the cis‐element of the IL1A gene was determined by electrophoretic mobility shift assay (EMSA).ResultsAffected fibroblasts exhibited a strong nuclear run‐on signal, indicative of constitutive transcription activity of the IL1A gene. Luciferase assay indicated high levels of transcription activity of pLuc.–1437 in transiently transfected fibroblasts from affected skin; this was absent in transiently transfected control fibroblasts. Analysis of constructs containing a series of 5′ deletions of pLuc.–1437 revealed that the sequence between −96 and −82 (nuclear factor–interleukin‐1α [NF–IL‐1α]) was the most important for transcription of the IL1A gene in affected SSc fibroblasts. NF–IL‐1α contains a 5′‐GGAA‐3′ sequence that is essential for specific binding of members of the Ets nuclear protein family. Using EMSA, a DNA protein complex was detected in samples containing nuclear extracts from affected fibroblasts and the NF–IL‐1α probe, whereas no specific band was detected in samples from normal fibroblasts. The DNA protein complex disappeared with the use of NF–IL‐1α probes that had mutations of the Ets binding sites.ConclusionThese findings suggest that a DNA binding protein containing the Ets domain is constitutively expressed only in fibroblasts from the affected skin of SSc patients and regulates the transcription of the IL1A gene, which contributes to the fibrogenic phenotype of fibroblasts in SSc.
Functional disability in rheumatoid arthritis patients compared with a community population in Finland
Authors: Sokka Tuulikki , Krishnan Eswar , Häkkinen Arja , Hannonen Pekka 
Published: January 2003

AbstractObjectiveTo compare Health Assessment Questionnaire (HAQ) scores of patients with rheumatoid arthritis (RA) with HAQ scores from a sex‐ and age‐adjusted population.MethodsPatients with RA (n = 1,095) and control subjects (n = 1,530) completed a mailed questionnaire that comprised the HAQ, pain and global health scores, education level, and comorbidities, as well as height, weight, and lifestyle attitudes, including smoking and exercise habits.ResultsThe HAQ scores increased (indicating declining function) with older age in patients and controls. The HAQ scores were above the reference values (>95th percentile of the HAQ scores of the age‐ and sex‐matched population) in 17–45% of women with RA and in 7–32% of men with RA ages 30–79 years, while the HAQ scores of the patients ≥80 years were similar to those of the age‐ and sex‐matched population. In a logistic regression model, the odds ratio for disability (HAQ score ≥1; at least some difficulties in most activities of daily living) was 7.7 (95% confidence interval 5.3–11.1; P < 0.001) among patients with RA compared with community controls, when adjusted for age, sex, education, smoking, exercise, body mass index, number of comorbidities, and pain.ConclusionRA is associated with a >7‐fold risk of disability compared with that in a general population of adults in the same community. The impact of disability due to RA appears to be greater in younger and middle‐age people than in elderly patients.
Control of fibroblast‐like synoviocyte proliferation by macrophage migration inhibitory factor
Authors: Lacey Derek , Sampey Annaleise , Mitchell Robert , Bucala Richard , Santos Lanie , Leech Michelle , Morand Eric 
Published: January 2003

AbstractObjectiveThe hyperplasia of fibroblast‐like synoviocytes (FLS) is considered essential to the evolution of joint destruction in rheumatoid arthritis (RA), but the mechanisms underlying FLS proliferation remain poorly understood. Macrophage migration inhibitory factor (MIF) is a cytokine that has recently been shown to exert proinflammatory effects on RA FLS. This study sought to identify the mechanisms of activation of FLS by MIF, and to assess the effects of MIF on synovial cell proliferation.MethodsHuman RA FLS were treated with recombinant MIF, interleukin‐1β (IL‐1β), tumor necrosis factor α (TNFα), and/or anti‐MIF monoclonal antibodies (mAb). Proliferation was measured with tritiated thymidine incorporation. Nuclear factor κB (NF‐κB) and mitogen‐activated protein (MAP) kinase activation were measured with immunohistochemistry and Western blotting, respectively.ResultsFLS proliferation was significantly increased by MIF. IL‐1β and TNFα also induced proliferation, but these effects were prevented by neutralization with anti‐MIF mAb. Activation of NF‐κB was induced by IL‐1β, but not by MIF. Anti‐MIF mAb had no effect on IL‐1β–induced NF‐κB nuclear translocation. By contrast, MIF induced phosphorylation of extracellular signal–regulated kinase (ERK) MAP kinase. ERK antagonism, but not NF‐κB antagonism, prevented the effect of MIF on FLS proliferation.ConclusionThese data suggest that MIF may regulate RA synovial hyperplasia by acting directly and via involvement in the effects of IL‐1β and TNFα. In addition, the effects of MIF on FLS activation are independent of NF‐κB, and dependent on ERK MAP kinase. These data suggest an important therapeutic potential for MIF antagonism in RA.
Increased salivary gland tissue expression of Fas, Fas ligand, cytotoxic T lymphocyte–associated antigen 4, and programmed cell death 1 in primary Sjögren's syndrome
Authors: Bolstad Anne Isine , Eiken Hans Geir , Rosenlund Benedikte , Alarcón‐Riquelme Marta E. , Jonsson Roland 
Published: January 2003

AbstractObjectiveTo assess salivary gland tissues obtained from patients with primary Sjögren's syndrome (SS) for the gene expression profile of the candidate genes TNFRSF6 (Fas), TNFSF6 (FasL), SSA1 (Ro52α and the splice variant Ro52β), SSB (La), CTLA4, PDCD1 (PD‐1), and ORM2, which were selected on the basis of their putative participation in salivary gland inflammation.MethodsQuantitative real‐time reverse transcriptase–polymerase chain reaction (RT‐PCR) was used to examine the expression of messenger RNA (mRNA). Tissue localization of the expressed proteins was detected by immunohistochemistry.ResultsExpression of mRNA was increased for Fas (5.1‐fold; P < 0.001), FasL (8.8‐fold; P < 0.05), cytotoxic T lymphocyte–associated antigen 4 (CTLA‐4) (11.2‐fold; P < 0.01), programmed cell death 1 (PD‐1) (15.2‐fold; P < 0.05), Ro52α (3.0‐fold; P < 0.01), La (2.3‐fold; P < 0.05), and orosomucoid 2 (ORM2) (4.4‐fold; P < 0.05) in patients compared with controls when GAPDH was used as endogenous standard in duplex runs. In single runs using 2 other endogenous standards (18S and β‐actin), statistically significant differences between patients and controls were confirmed for expression of Fas, FasL, CTLA‐4, and PD‐1, but this difference was not observed for Ro52α, La, and ORM2. Expression of Ro52β mRNA was similar in patients and controls.ConclusionThe present study demonstrates a substantial increase in expression of the negative regulator molecules PD‐1 and CTLA‐4 and the apoptotic signal molecules Fas and FasL in patients with primary SS compared with controls, which corresponded to the immunomorphologic pattern. The results strongly indicate that these molecules have central roles in the inflammatory process in the salivary glands of patients with primary SS.
Screening for atherosclerosis in patients with rheumatoid arthritis: Comparison of two in vivo tests of vascular function
Authors: Van Doornum S. , McColl G. , Jenkins A. , Green D. J. , Wicks I. P. 
Published: January 2003

AbstractObjectiveInflammation appears to play a central role in atherosclerosis, and endothelial damage mediated by systemic inflammation may contribute to the increased cardiovascular mortality in rheumatoid arthritis (RA). Brachial artery flow‐mediated dilatation (FMD) and pulse wave analysis (PWA) are measures of vascular function. The aim of this study was to determine if FMD and PWA are abnormal in patients with RA.MethodsTwenty‐five RA patients and 25 matched healthy controls were studied. All were free of traditional cardiovascular risk factors. FMD was measured in all subjects. PWA was performed in 18 RA patients and 18 controls, with results expressed as large and small artery compliance (C1 and C2). Modified Sharp scores were calculated in 13 RA patients.ResultsResults (mean ± SD) in RA patients and controls, respectively, were as follows: FMD 107.6 ± 4.6% versus 108.5 ± 4.1% (P = 0.49), C1 14.8 ± 2.8 ml/mm Hg × 10 versus 17.9 ± 3.1 ml/mm Hg × 10 (P = 0.0033), C2 4.5 ± 2.3 ml/mm Hg × 100 versus 7.7 ± 3.7 ml/mm Hg × 100 (P = 0.0039). There was an inverse correlation between C2 and modified Sharp scores in the RA patients (Spearman's rho −0.69, P = 0.0085).ConclusionFMD was normal in these RA patients, whereas arterial compliance was markedly reduced. PWA appears to be a more sensitive measure of vascular dysfunction than FMD in RA and may be the preferred surrogate marker of vascular dysfunction in longitudinal studies of RA patients. The inverse correlation between C2 and the modified Sharp score, a measure that reflects disease activity over time, supports the notion that chronic inflammation plays a role in RA‐associated atherosclerosis.
Association of IL1A gene polymorphisms with susceptibility to and severity of systemic sclerosis in the Japanese population
Authors: Kawaguchi Yasushi , Tochimoto Akiko , Ichikawa Naomi , Harigai Masayoshi , Hara Masako , Kotake Shigeru , Kitamura Yutaka , Kamatani Naoyuki 
Published: January 2003

AbstractObjectiveTo analyze the frequencies of haplotypes of single‐nucleotide polymorphisms (SNPs) of the IL1A gene (at −889, +4729, and +4845) in patients with systemic sclerosis (SSc) and in healthy control subjects, and to determine whether the IL1A gene haplotype is associated with SSc susceptibility or disease severity.MethodsWe studied 60 patients with SSc (34 with diffuse cutaneous SSc and 26 with limited cutaneous SSc) and 70 healthy control subjects. Polymorphisms of the IL1A gene were genotyped by direct sequencing using the ABI Prism 377 Sequence Detection System. The LDSupport program, which was recently developed in our laboratory, was used to estimate the haplotype frequencies of SNPs in the study population.ResultsWe confirmed the presence of 2 SNPs at positions −889 (C/T) and +4845 (G/T) of the IL1A gene, as previously reported. We also identified a novel SNP at position +4729 (T/C). Six haplotypes, CTG (49.7%), TCT (14.7%), CCT (20.3%), TTG (13.2%), CCG (1.4%), and TTT (0.7%), were found in the healthy controls. In contrast, only 2 haplotypes, CTG (95%) and TCT (5%), were detected in the SSc patients. Notably, the CTG haplotype was present at a significantly higher frequency in the SSc patients than in the healthy controls (P < 0.0001). We also examined the relationship between the CTG/CTG diplotype frequencies and interstitial lung disease (ILD), a major complication of SSc, as an indicator of disease severity. All SSc patients with ILD had the CTG/CTG diplotype, whereas the frequency of this diplotype was only 67% in patients without ILD.ConclusionOur observations suggest that the CTG haplotype of the IL1A gene may be an important marker for the susceptibility to, and the severity of, SSc.
Serum amyloid P component binds to late apoptotic cells and mediates their uptake by monocyte‐derived macrophages
Authors: Bijl Marc , Horst Gerda , Bijzet Johan , Bootsma Hendrika , Limburg Pieter C. , Kallenberg Cees G. M. 
Published: January 2003

AbstractObjectiveSome pentraxins, such as C‐reactive protein, bind to apoptotic cells and are involved in the clearance of these cells. We undertook this study to determine whether serum amyloid P component (SAP; a pentraxin that, when deficient in mice, results in lupus‐like disease) binds to apoptotic cells and to assess the functional consequences of SAP binding for their phagocytosis by macrophages.MethodsHuman peripheral blood monocytes were isolated and cultured for 7 days to obtain monocyte‐derived macrophages. Jurkat cells were irradiated with ultraviolet B to induce apoptosis. After 4 hours, a mean ± SEM of 54.0 ± 5.1% of these cells stained with annexin V and were propidium iodide negative (early apoptotic [EA] cells). After 24 hours, 77.3 ± 2.7% of cells stained positive with both annexin V and propidium iodide (late apoptotic [LA] cells or secondary necrotic cells). EA and LA cells were incubated with fluorescein isothiocyanate–labeled SAP in the presence or absence of Ca2+, and binding was measured by flow cytometry. Phagocytosis was tested by incubation of macrophages with EA or LA cells in the presence of normal human serum (NHS) and quantified as a phagocytosis index (PI; number of Jurkat cells internalized by 100 macrophages). Experiments were repeated with SAP‐depleted serum and after reconstitution with increasing concentrations of SAP.ResultsThe majority of LA cells did bind SAP in the presence of Ca2+, whereas EA cells did not. SAP depletion of NHS resulted in a 50% decrease in the PI for LA cells, and complete restoration of the PI could be demonstrated with SAP reconstitution up to 100 μg/ml. SAP depletion had no effect on phagocytosis of EA cells.ConclusionSAP binds to LA cells and is involved in the phagocytosis of these cells by human monocyte–derived macrophages. This may have consequences for diseases such as systemic lupus erythematosus, in which phagocytosis of apoptotic cells is decreased.