bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of interleukin‐18 in experimental group B streptococcal arthritis
Authors: Tissi Luciana , McRae Bradford , Ghayur Tariq , von Hunolstein Christina , Orefici Graziella , Bistoni Francesco , Puliti Manuela 
Published: June 2004

AbstractObjectiveTo assess the role of interleukin‐18 (IL‐18) in the evolution of septic arthritis induced by group B streptococci (GBS) in mice.MethodsCD1 mice were inoculated intravenously with 8 × 106 colony‐forming units (CFU) of type IV GBS (strain 1/82), and administered intraperitoneally 1 hour before infection with anti–IL‐18 monoclonal antibodies (0.25 mg/mouse). In a subsequent set of experiments, mice infected with a suboptimal arthritogenic dose of GBS (4 × 106 CFU/mouse) were administered different doses of recombinant IL‐18 for 4 days, starting 1 hour after infection. Mortality, evolution of arthritis, bacterial clearance, joint histopathology, and cytokine production were examined in infected mice that did or did not receive treatment with anti–IL‐18 antibodies or IL‐18.ResultsIL‐18 was produced during GBS infection. Neutralization of IL‐18 resulted in a decrease in mortality rates, and in the incidence and severity of arthritis. Amelioration of arthritis was accompanied by a dramatic reduction in local IL‐1β, IL‐6, macrophage inflammatory protein 1α (MIP‐1α) and MIP‐2 production, and reduced bacterial burden. Administration of exogenous IL‐18 resulted in increased mortality rates and increased incidence and severity of GBS arthritis, concomitant with a higher number of GBS and increased levels of IL‐6, IL‐1β, MIP‐1β, and MIP‐2 production in the joints.ConclusionThe present study indicated some involvement of IL‐18 in the pathogenesis of GBS‐induced arthritis. The role of IL‐18 in joint pathology is shown by a regulatory effect on inflammatory mediator levels and local cell influx. Thus, IL‐18 should be regarded as a potential therapeutic target in GBS infection and arthritis.
Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis
Authors: Benito Maria J. , Murphy Eithne , Murphy Evelyn P. , van den Berg Wim B. , FitzGerald Oliver , Bresnihan Barry 
Published: June 2004

AbstractObjectiveTo compare the expression of the Rel/NF‐κB subunits, NF‐κB1 (p50) and RelA (p65), in paired synovial tissue samples selected from sites adjacent to and remote from the cartilage–pannus junction (CPJ) in patients with inflammatory arthritis.MethodsSynovial tissue was selected at arthroscopy from sites adjacent to the CPJ and from the suprapatellar pouch of patients who were referred to an early arthritis clinic. Tissue samples from patients with osteoarthritis (OA) undergoing knee arthroplasty were also studied. Rel/NF‐κB subunit activation and expression were measured by electrophoretic mobility shift assay and supershift analyses and by immunohistochemistry.ResultsTissue samples were obtained from 10 patients with rheumatoid arthritis (RA), 7 with a seronegative arthropathy (SnA), and 6 with OA. Rel/NF‐κB was abundantly expressed in all samples. In both RA and SnA synovial tissue, the absolute number of NF‐κB1+ cells at the CPJ was significantly higher than at non‐CPJ sites (P = 0.006 and P = 0.02, respectively). The proportion of cells expressing NF‐κB1 was also significantly higher at the CPJ compared with non‐CPJ sites (P = 0.003 in RA, P = 0.009 in SnA). The numbers of RelA+ cells were consistently lower throughout. In RA synovial tissue, but not in SnA synovial tissue, both the absolute number and the proportion of RelA+ cells were significantly higher at the CPJ than at non‐CPJ sites (P = 0.003 and P = 0.01, respectively). In OA synovial tissue, the numbers of cells expressing NF‐κB1 and RelA were similar to those observed at the non‐CPJ sites in all inflammatory tissues studied.ConclusionIn this study of early inflammatory arthritis, expression of NF‐κB1 in synovial tissue was highest at sites most likely to be associated with joint erosion. These observations are consistent with a critical role of NF‐κB1 in joint destruction, and support the rationale for specific therapeutic inhibition of NF‐κB in RA.
Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system
Authors: Napirei Markus , Wulf Swantje , Mannherz Hans Georg 
Published: June 2004

AbstractObjectiveDnase1‐deficient mice with the 129 × C57BL/6 genetic background develop symptoms of systemic lupus erythematosus, such as high titers of antinuclear autoantibodies directed against nucleosomes. In this study we analyzed a potential molecular pathomechanism leading to this autoimmunity, by exploring the influence of extracellular Dnase1 present in serum on the breakdown of chromatin in necrotic cells in vitro.MethodsHuman breast adenocarcinoma cells (MCF‐7) and other cell lines were subjected to necrosis induced by hydrogen peroxide, streptolysin O, or freeze‐thawing. Subsequently, the influence of sera from Dnase1‐deficient and wild‐type mice as well as the influence of purified enzymes present in the culture medium on the process of necrotic chromatin breakdown was investigated.ResultsNecrotic chromatin breakdown resembled apoptotic DNA laddering and was catalyzed by serum Dnase1 in conjunction with plasmin. During necrosis, Dnase1 and plasminogen penetrated the cell and accumulated in the cytoplasm and nucleus. Plasminogen bound to the cytoskeleton and nuclear structures, was activated to plasmin by either tissue‐type or urokinase‐type plasminogen activator, and degraded histone H1, thereby facilitating internucleosomal DNA cleavage by Dnase1.ConclusionOur results suggest that serum Dnase1 in cooperation with the plasminogen system guarantees a fast and effective breakdown of chromatin during necrosis by the combined cleavage of DNA as well as of DNA binding proteins. The failure of such a clearance mechanism might lead to antinuclear autoimmunity similar to that observed in the Dnase1‐deficient mouse.
Altered blood B lymphocyte homeostasis in systemic sclerosis: Expanded naive B cells and diminished but activated memory B cells
Authors: Sato Shinichi , Fujimoto Manabu , Hasegawa Minoru , Takehara Kazukiko 
Published: June 2004

AbstractObjectiveTo determine phenotypic and functional abnormalities of blood B cell subsets in patients with systemic sclerosis (SSc).MethodsCell surface marker expression was determined by flow cytometry. Spontaneous apoptosis was evaluated by annexin V expression with flow cytometric analysis. IgG production by isolated IgD− memory B cells was examined by enzyme‐linked immunosorbent assay.ResultsThe numbers of blood CD27− naive B cells from SSc patients were increased compared with normal control cells, while memory B cells expressing medium levels of CD27 and plasmablasts expressing high levels of CD27 were reduced. In contrast, plasmablasts were the predominant population in patients with systemic lupus erythematosus (SLE). Memory B cells in SSc showed increased expression of activation markers, including CD80, CD86, and CD95, relative to normal controls. Consistent with CD95 up‐regulation, SSc memory B cells exhibited augmented spontaneous apoptosis after 24‐hour incubation; augmented apoptosis may explain the reduced memory B cell number. Nonetheless, isolated IgD− SSc memory B cells treated with stimuli had an enhanced ability to produce IgG. Furthermore, expression of CD19, a critical signal transduction molecule of B cells that regulates autoantibody production, was significantly increased in memory B cells as well as in naive B cells in SSc. In contrast, CD19 expression was decreased in SLE B cells.ConclusionSSc patients have distinct abnormalities of blood homeostasis and B cell compartments, characterized by expanded naive B cells and activated but diminished memory B cells. Our results suggest that CD19 overexpression in SSc memory B cells is related to their hyperreactivity.
Up‐regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis
Authors: Galligan Carole L. , Matsuyama Wataru , Matsukawa Akihiro , Mizuta Hiroshi , Hodge David R. , Howard O. M. Zack , Yoshimura Teizo 
Published: June 2004

AbstractObjectiveRheumatoid arthritis (RA) is a chronic inflammatory condition characterized by a cellular influx and destruction of the joint architecture. Chemokines characteristically regulate leukocyte recruitment and activation. Chemokine (CC motif) receptor–like 2 (CCRL2) is an orphan receptor with homology to other CC chemokine receptors. We undertook this study to examine CCRL2 expression in RA, cytokine regulation of expression, and the source of a putative ligand in an attempt to determine the role of this receptor during inflammation.MethodsExpression of CCRL2 on joint‐infiltrating leukocytes was examined by immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary neutrophils using Northern and Western blotting and reverse transcriptase–polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2 (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system, and their migration in response to fractions of synovial fluid (SF) from RA patients was examined using a 48‐well chamber.ResultsCCRL2 expression was observed on all infiltrating neutrophils and on some macrophages obtained from the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that CCRL2 messenger RNA (mRNA) was rapidly up‐regulated following stimulation with lipopolysaccharide (1 μg/ml) or tumor necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were expressed in cytokine‐stimulated neutrophils. Cells expressing either of these splice variants migrated in response to a fraction of RA SF.ConclusionCCRL2 expression is up‐regulated on synovial neutrophils of RA patients. Inflammatory products present in the SF activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of RA.
Abnormalities in peripheral B cell memory of patients with primary Sjögren's syndrome
Authors: Hansen Arne , Gosemann Mirko , Pruss Axel , Reiter Karin , Ruzickova Sarka , Lipsky Peter E. , Dörner Thomas 
Published: June 2004

AbstractObjectiveTo delineate disturbances in peripheral B cell memory in primary Sjögren's syndrome (SS).MethodsIsotype‐specific immunoglobulin (Ig) heavy‐chain transcripts were analyzed in single‐sorted CD19+,CD27− naive and CD19+,CD27+ memory B cells from patients with primary SS and normal healthy control subjects.ResultsA significantly higher frequency of B cells expressing μ‐, α‐, and/or γ‐chain transcripts were found in patients with primary SS compared with controls (58.0% versus 14.3%; P < 0.0001). Notably, 30.5% of individual B cells (for primary SS, 38.7%; for controls, 12.7% [P < 0.0001]) simultaneously expressed transcripts for different Ig heavy‐chain isotypes using identical VH–D–JH rearrangements. However, these cells lacked surface expression of more than one of the respective Ig heavy‐chain isotypes as well as messenger RNA (mRNA) transcripts for 2 germinal center markers, activation‐induced cytidine deaminase, and Bcl‐6. In contrast with the findings in normal healthy controls, peripheral B cell memory in patients with primary SS was characterized by 1) circulating CD27+ B cells expressing heavily mutated Ig VH transcripts (mutational frequency 8.6% versus 4.3%; P < 0.0001), 2) significantly enhanced mutational frequencies of Cμ transcripts (9.6% versus 2.5%; P < 0.0001), 3) a high proportion (61.2%) of CD27+ B cells expressing transcripts for multiple Ig heavy‐chain isotypes, and 4) a CD27− memory‐type B cell subpopulation expressing mutated Cμ transcripts.ConclusionAltogether, both B cell hyperactivity and striking abnormalities in peripheral B cell memory are indicated at the single‐cell mRNA level in patients with primary SS. Detection of multiple Ig heavy‐chain transcripts in peripheral CD19+,CD27+ memory B cells of patients with SS may represent the abnormal retention of pre‐switch mRNA transcripts in circulating post‐switch B cells.
The safety of anakinra in high‐risk patients with active rheumatoid arthritis: Six‐month observations of patients with comorbid conditions
Authors: Schiff Michael H. , DiVittorio Gino , Tesser John , Fleischmann Roy , Schechtman Joy , Hartman Sanford , Liu Thomas , Solinger Alan M. 
Published: June 2004

AbstractObjectiveTo determine in a placebo‐controlled, double‐blind trial the safety profile of daily anakinra (Kineret) use in patients with active rheumatoid arthritis (RA) and concurrent comorbid conditions.MethodsIn 169 centers in 9 countries, 1,414 patients with active RA were randomly assigned to receive either anakinra (100 mg) or placebo treatment (4:1 anakinra‐to‐placebo allocation ratio), with study drug administered by daily subcutaneous injection for 6 months. The current post hoc analysis assessed baseline comorbid conditions, and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following: cardiovascular event, pulmonary event, central nervous system–related event, infection, diabetes, malignancy, or renal impairment. Within each treatment group (anakinra or placebo), incidence rates were summarized for serious adverse events, infectious events, and serious infectious events in high‐risk patients and compared with these incidence rates in patients without comorbid conditions.ResultsThe majority of patients in the trial had one or more comorbid conditions. In these high‐risk patients, there were no differences in the incidence of serious adverse events or infectious events between treatment groups. The incidence of serious infectious events with anakinra use was similar between high‐risk patients (2.5%) and the entire study population (2.1%) and was not attributable to any single comorbidity.ConclusionResults of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high‐risk patient population.
Association of the PD‐1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope
Authors: Prokunina Ludmila , Padyukov Leonid , Bennet Anna , de Faire Ulf , Wiman Björn , Prince Jonathan , Alfredsson Lars , Klareskog Lars , Alarcón‐Riquelme Marta 
Published: June 2004

AbstractObjectiveTo study the frequency of allele A of polymorphism PD‐1.3 of the PDCD1 gene in patients with rheumatoid arthritis (RA) and its subsets, based on the presence of rheumatoid factor (RF) and the shared epitope (SE) alleles.MethodsA total of 1,175 patients with RA and 3,404 controls were genotyped for the PD‐1.3 A/G polymorphism, which previously was identified as being involved in susceptibility to systemic lupus erythematosus (SLE) in patients of European descent.ResultsWe first detected a trend for association of allele A of the single‐nucleotide polymorphism PD‐1.3 with RA (P = 0.053, odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.99–1.41). To further clarify the nature of this association, patients with RA were divided into 4 groups according to the presence of RF and the SE alleles. Association was found only in the group of patients negative for both RF and the SE alleles (P = 0.0054 [corrected P = 0.015], OR 1.75, 95% CI 1.15–2.65).ConclusionPatients negative for both RF and the SE alleles showed association with the same allele that we previously identified as being involved in susceptibility to SLE. These results provide the first evidence of the involvement of the human PDCD1 gene in arthritis.
Induction of arthritis in HLA–DR4–humanized and HLA–DQ8–humanized mice by human cartilage proteoglycan aggrecan but only in the presence of an appropriate (non‐MHC) genetic background
Authors: Szántó Sándor , Bárdos Tamás , Szabó Zoltán , David Chella S. , Buzás Edit I. , Mikecz Katalin , Glant Tibor T. 
Published: June 2004

AbstractObjectiveTo determine whether the rheumatoid arthritis (RA)–predisposing class II molecules of the major histocompatibility complex (MHC) can present cartilage proteoglycan (PG) aggrecan, and if so, to determine the epitope repertoire of the human cartilage PG in HLA‐transgenic mice and determine whether HLA‐transgenic mice develop arthritis in response to immunization with human cartilage PG.MethodsMice transgenic for HLA–DR2.Ab0, DR3.Ab0, DR4.Ab0, and DQ8.Ab0, lacking their own (mouse) class II antigens (Ab0), on the original (arthritis‐resistant) and the arthritis‐susceptible BALB/c backgrounds, were immunized with human cartilage PG. The T cell epitope repertoire presented by these class II MHC alleles was determined using a synthetic peptide library (143 peptides of the core protein of human cartilage PG), and arthritis development was monitored and compared in wild‐type and HLA‐transgenic/congenic BALB/c mice.ResultsMice of the 4 HLA‐transgenic lines, either on the original mixed, arthritis‐resistant background or DR4.Ab0‐ and DQ8.Ab0‐transgenic/congenic mice on the arthritis‐susceptible BALB/c genetic background, responded well to PG immunization (as assessed by T cell responses and antibody and cytokine production), and a number of T cell epitopes along the core protein of human cartilage PG were identified. DR4.Ab0‐ and DQ8.Ab0‐transgenic mice immunized with human cartilage PG developed arthritis, but only when these class II MHC molecules were present on the arthritis‐susceptible (BALB/c) genetic background.ConclusionA number of human cartilage PG epitopes can be presented by HLA alleles that predispose to the development of RA, but the epitopes of the cartilage PG presented by HLA–DR4 or HLA–DQ8 can induce arthritis only in the presence of an appropriate genetic (non‐MHC) background.
Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium
Authors: Westman M. , Korotkova M. , Klint E. af , Stark A. , Audoly L. P. , Klareskog L. , Ulfgren A.‐K. , Jakobsson P.‐J. 
Published: June 2004

AbstractObjectiveMicrosomal prostaglandin E synthase 1 (mPGES‐1) catalyzes the formation of PGE2 from cyclooxygenase‐derived PGH2. Microsomal PGES‐1 is induced by proinflammatory cytokines and is strongly linked to conditions that result in high PGE2 biosynthesis. PGE2 contributes to the pathogenesis of rheumatoid arthritis (RA), acting as a mediator of inflammation and promoting bone destruction. Induction of mPGES‐1 in rheumatoid synoviocytes by proinflammatory cytokines has been demonstrated in vitro, indicating an important role in RA pathogenesis. Recent studies using mPGES‐1–deficient mice demonstrated the importance of this gene in chronic inflammation. The aim of this study was to investigate the expression and localization of mPGES‐1 in synovial biopsy specimens obtained from patients with RA.MethodsSynovial tissue samples from 24 patients with RA were obtained, and immunohistologic analysis was performed using polyclonal antibodies against mPGES‐1. Double immunofluorescence staining was performed with antibodies to CD3, CD19, CD20, CD68, CD163, and prolyl 4‐hydroxylase.ResultsIntracellular mPGES‐1 staining was observed in synovial membranes from all of the RA patients studied. Specifically, strong expression of mPGES‐1 was detected in synovial lining cells. In sublining mononuclear and fibroblast‐like cells, the extent of mPGES‐1 staining was less than that in the synovial lining cells. In some patients, positive staining was observed in endothelial cells. With the double immunofluorescence technique, mPGES‐1 production was detected in synovial macrophages and fibroblasts, while mPGES‐1 expression was not observed in lymphocytes.ConclusionThe demonstration of mPGES‐1 expression in synovial tissues from patients with RA suggests a role for mPGES‐1 in the RA disease process. Microsomal PGES‐1 might be a potential new target for treatment strategies to control PGE2 synthesis in patients with RA, without the systemic side effects associated with cyclooxygenase inhibitors.
Control of spontaneous B lymphocyte autoimmunity with adenovirus‐encoded soluble TACI
Authors: Liu Weimin , Szalai Alex , Zhao Limin , Liu Di , Martin Flavius , Kimberly Robert P. , Zhou Tong , Carter Robert H. 
Published: June 2004

AbstractObjectiveSerum B lymphocyte stimulator (BLyS) is increased in autoimmune diseases, both in animal models and in humans. This study examined the effect of BLyS blockade in 3 animal models of lupus.MethodsAntibodies and lupus‐like disease manifestations were examined in mice after administration of a single injection of an adenoviral construct for the transmembrane activator and CAML interactor receptor (AdTACI) that produces high serum levels of TACI‐Fc fusion protein.ResultsIn C57BL/6 (B6) lpr/lpr mice (B6.lpr/lpr), which were used to model autoimmunity in the absence of severe disease, treatment of younger mice with AdTACI prevented the development of hypergammaglobulinemia. In contrast, use of AdTACI for BLyS blockade had only transient effects on the levels of IgG in normal B6 mice. AdTACI blocked the development of autoantibodies in younger B6.lpr/lpr mice and reversed the production of autoantibodies in older B6.lpr/lpr mice, and also reduced the numbers of splenic plasma cells. In MRL.lpr/lpr mice, which were used to examine disease manifestations, AdTACI reduced the extent of glomerulonephritis and proteinuria and improved survival, but had little effect on T cell infiltration and interstitial nephritis. However, in (NZB × NZW)F1 mice, AdTACI induced neutralizing anti‐TACI antibodies and failed to reduce the numbers of B cells.ConclusionBLyS blockade has little effect on IgG levels in normal mice, but reverses the production of spontaneously produced IgM and IgG autoantibodies in the setting of established autoimmunity. Blockade of BLyS ameliorates B cell–dependent disease manifestations even in the MRL.lpr/lpr model, but its effectiveness on autonomous T cell aspects of the disease is limited. Moreover, its effectiveness is neutralized by anti‐TACI antibodies when present. These results provide a basis for understanding the potential effects of BLyS blockade in human disease.
Health‐related quality of life in systemic sclerosis as measured by the short form 36: Relationship with clinical and biologic markers
Authors: Del Rosso Angela , Boldrini Maura , D'Agostino David , Placidi Giovanni Plinio Augusto , Scarpato Alessandra , Pignone Alberto , Generini Sergio , Konttinen Yrio , Zoppi Massimo , Vlak Tonko , Placidi Gianfranco , Matucci‐Cerinic Marco 
Published: June 2004

AbstractObjectiveTo evaluate health‐related quality of life (HRQOL) in patients with systemic sclerosis (SSc) using the Short Form 36 (SF‐36) and to correlate SF‐36 scores with clinical and biologic markers.MethodsThe SF‐36 was administered to 24 controls and 24 SSc patients. SSc patients also were evaluated for subset (limited SSc [lSSc] and diffuse SSc [dSSc]), age, disease duration, angiotensin‐converting enzyme (ACE) levels, autoantibodies, and skin and internal organ involvement.ResultsThe physical summary score (PSS) was lower in SSc patients than in controls (P < 0.05), whereas the mental summary score (MSS) was higher in dSSc than in lSSc patients (P < 0.05). Five of 8 single SF‐36 domain scores were lower in SSc patients than in controls (P < 0.05). Vitality was higher in dSSc than in controls (P < 0.001). In SSc, elder age correlated with lower PSS; low ACE levels and high skin score correlated with higher general mental health and role limitations due to physical problems, respectively (P < 0.05). Patients with heart involvement had higher scores in general health perceptions (P < 0.05).ConclusionThe SF‐36 shows that HRQOL is impaired in patients with SSc. Higher scores in MSS and vitality in patients with dSSc and correlations of high SF‐36 scores with specific organ involvement suggest that SSc patients with severe disease are more able to cope with HRQOL modification.