bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of subchondral bone marrow in rheumatoid arthritis: Lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment
Authors: Bugatti Serena , Caporali Roberto , Manzo Antonio , Vitolo Barbara , Pitzalis Costantino , Montecucco Carlomaurizio 
Published: October 2005

AbstractObjectiveTo evaluate the presence and immunohistochemical characteristics of subchondral bone marrow inflammatory infiltrate in rheumatoid arthritis (RA) and to determine the in situ relationship between marrow inflammation and osteoclast recruitment.MethodsBone samples and paired synovia from 8 RA patients undergoing joint surgery were analyzed by immunohistochemistry and in situ hybridization for specific lymphoid neogenetic features, such as T and B cell composition, follicular dendritic cell (FDC) networks, peripheral lymph node addressin (PNAd)–positive high endothelial venules, and lymphoid chemokine expression. Osteoclasts were identified as multinucleated tartrate‐resistant acid phosphatase (TRAP)–positive and cathepsin K–positive cells adherent to the bone surface.ResultsAn inflammatory infiltrate with perivascular aggregates of variable size was detected in 7 (87.5%) of 8 synovial samples and in paired bone samples. Lymphoid neogenetic features typical of rheumatoid synovium were also recognized in the bone marrow. PNAd+ blood vessels were found in 4 of 8 patients, CD21+ FDC networks in 2 patients, CXCL13+ cells in 5 patients, and CCL21+ cells in 6 patients. TRAP‐positive and cathepsin K–positive osteoclasts were identified on both the synovial and marrow sides of the bone surface. Bone marrow samples showing a higher degree of inflammation were characterized by a significantly increased number of osteoclasts adherent to the subchondral bone.ConclusionOur data demonstrate that lymphoid aggregates with lymphoid neogenetic features are detectable on the subchondral side of the joint in established RA. Moreover, the local inflammation/aggregation process appears to be related to osteoclast differentiation on the marrow side of subchondral bone, supporting a functional role of the bone compartment in local damage.
Inhibition of lupus disease by anti–double‐stranded DNA antibodies of the IgM isotype in the (NZB × NZW)F1 mouse
Authors: Werwitzke Sonja , Trick David , Kamino Kenji , Matthias Torsten , Kniesch Katja , Schlegelberger Brigitte , Schmidt Reinhold E. , Witte Torsten 
Published: October 2005

AbstractObjectiveIn systemic lupus erythematosus (SLE), immune complexes (ICs) containing pathogenic IgG anti–double‐stranded DNA (anti‐dsDNA) autoantibodies are deposited in renal capillaries and initiate glomerulonephritis (GN) by the activation of complement and effector cells. In contrast, it has been demonstrated that the presence of IgM anti‐dsDNA antibodies correlates negatively with the development of GN in SLE. The aim of this study was to determine whether anti‐dsDNA antibodies of the IgM isotype protect against IC‐mediated organ damage in SLE.MethodsLupus‐prone (NZB × NZW)F1 mice (females) were treated with murine monoclonal IgM anti‐dsDNA antibodies. Treatment was delivered by subcutaneous injection at a dosage of 100 μg/week starting at 16 weeks of age (prophylactic) or at 24 weeks of age (therapeutic).ResultsMice treated with IgM anti‐dsDNA exhibited a delayed onset of proteinuria and a reduced degree of renal pathology, which resulted in significantly improved survival as compared with control mice. Serum concentrations of IgG anti‐dsDNA antibodies were not significantly modified. However, glomerular deposition of ICs was markedly reduced in both treatment protocol groups. In contrast, higher amounts of IgG and IgM and increased expression of Fcγ receptor were demonstrated in liver sections from the treated mice compared with the untreated mice, suggesting an enhanced clearance of soluble ICs from phagocytic cells of the reticuloendothelial system.ConclusionThese data demonstrate the efficacy of IgM anti‐dsDNA treatment in inhibiting the pathologic changes of lupus in (NZB × NZW)F1 mice. Lower glomerular IC deposition is associated with a reduced inflammatory response and impaired organ damage. The reduced frequency of GN in SLE patients who have IgM anti‐dsDNA antibodies may therefore reflect a disease‐modifying effect of this class of autoantibodies that has potential therapeutic implications. Our findings should encourage the development of new therapeutic modalities using IgM anti‐dsDNA antibodies in humans with SLE.
The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis
Authors: Giusti Betti , Serratì Simona , Margheri Francesca , Papucci Laura , Rossi Luciana , Poggi Filippo , Magi Alberto , Del Rosso Angela , Cinelli Marina , Guiducci Serena , Kahaleh Bashar , Matucci‐Cerinic Marco , Abbate Rosanna , Fibbi Gabriella , Del Rosso Mario 
Published: October 2005

AbstractObjectivePostnatal angiogenesis relies on a proper response of endothelial cells to angiogenic stimuli. In systemic sclerosis (SSc), endothelial cells are unresponsive to angiogenic factors. Since circumstantial and experimental evidence points to tissue kallikreins as powerful effectors of the angiogenic response, we undertook this study to investigate the kallikrein pattern of normal and SSc endothelial cells in order to identify differences that can account for defective angiogenesis.MethodsExpression of 14 tissue kallikreins was studied by a microarray approach, by reverse transcription–polymerase chain reaction, and by Western blotting in endothelial cells isolated from the skin of clinically healthy subjects and SSc patients. Cell proliferation was quantified by direct cell counting. Invasion and capillary morphogenesis were evaluated in a Boyden chamber and in culture flasks layered with Matrigel. Cyclic nucleotide production was measured by enzyme immunoassay. MAP kinase and ERK activation were measured by Western blotting.ResultsEndothelial cells from SSc patients showed poor expression of kallikreins 9, 11, and 12 compared with endothelial cells from normal subjects. Antibodies against the relevant kallikreins on normal endothelial cells revealed that while kallikreins 9, 11, and 12 induced cell growth, only kallikrein 12 regulated invasion and capillary morphogenesis. Buffering of kallikrein 12 with antibodies resulted in the acquisition of an SSc‐like pattern by normal cells in in vitro angiogenesis. Reduction of cAMP and cGMP production and of ERK phosphorylation upon administration of antikallikrein antibodies revealed that the activity of kallikreins 9, 11, and 12 was mediated by kinins.ConclusionReduction of tissue kallikreins 9, 11, and 12 may be relevant to reduced angiogenesis in SSc patients.
Utility of corticosteroid injection for temporomandibular arthritis in children with juvenile idiopathic arthritis
Authors: Arabshahi Bita , Dewitt Esi Morgan , Cahill Ann Marie , Kaye Robin D. , Baskin Kevin M. , Towbin Richard B. , Cron Randy Q. 
Published: October 2005

AbstractObjectiveTo assess the effects of computed tomography (CT)–guided injection of corticosteroid into the temporomandibular joint (TMJ) in children with juvenile idiopathic arthritis (JIA) and clinical and magnetic resonance imaging (MRI) evidence of TMJ inflammation.MethodsTwenty‐three children ages 4–16 years with JIA and MRI evidence of TMJ inflammation received CT‐guided TMJ injections of corticosteroid (triamcinolone acetonide [n = 16] or triamcinolone hexacetonide [n = 7]). Jaw pain or dysfunction and maximal incisal opening (MIO) distance were assessed before and after injection. Fourteen patients had followup MRI studies of the TMJ 6–12 months after injection.ResultsOf the 13 patients with symptoms of jaw pain prior to corticosteroid treatment, 10 (77%) had complete resolution of pain (P < 0.05). Prior to corticosteroid injection, MIO in all 23 patients was below age‐matched normal values. After injection, the MIO was improved by at least 0.5 cm in 10 patients (43%) (P = 0.0017). Patients under 6 years of age at the time of injection showed the best response, with a postinjection MIO similar to that in age‐matched controls (P = 0.2267). There was involvement of 23 TMJs in the 14 patients who had followup MRI studies; resolution of effusions was observed in 11 (48%) of the TMJs. Other than short‐term facial swelling in 2 patients, there were no side effects.ConclusionThe majority of children with symptomatic TMJ arthritis improved after intraarticular corticosteroid injection. Approximately half the patients experienced significant improvement in MIO and TMJ effusion. These data suggest that corticosteroid injection may be a useful procedure for the prevention and treatment of morbidities associated with TMJ arthritis in JIA.
Extracellular superoxide dismutase and oxidant damage in osteoarthritis
Authors: Regan Elizabeth , Flannelly Joanne , Bowler Russell , Tran Karen , Nicks Michael , Carbone Beth Duda , Glueck Deborah , Heijnen Harry , Mason Roger , Crapo James 
Published: October 2005

AbstractObjectiveTo use human cartilage samples and a mouse model of osteoarthritis (OA) to determine whether extracellular superoxide dismutase (EC‐SOD) is a constituent of cartilage and to evaluate whether there is a relationship between EC‐SOD deficiency and OA.MethodsSamples of human cartilage were obtained from femoral heads at the time of joint replacement surgery for OA or femoral neck fracture. Samples of mouse tibial cartilage obtained from STR/ort mice and CBA control mice were compared at 5, 15, and 35 weeks of age. EC‐SOD was measured by enzyme‐linked immunosorbent assay, Western blotting, and immunohistochemistry techniques. Real‐time quantitative reverse transcription–polymerase chain reaction was used to measure messenger RNA for EC‐SOD and for endothelial cell, neuronal, and inducible nitric oxide synthases. Nitrotyrosine formation was assayed by Western blotting in mouse cartilage and by fluorescence immunohistochemistry in human cartilage.ResultsHuman articular cartilage contained large amounts of EC‐SOD (mean ± SEM 18.8 ± 3.8 ng/gm wet weight of cartilage). Cartilage from patients with OA had an ∼4‐fold lower level of EC‐SOD compared with cartilage from patients with hip fracture. Young STR/ort mice had decreased levels of EC‐SOD in tibial cartilage before histologic evidence of disease occurred, as well as significantly more nitrotyrosine formation at all ages studied.ConclusionEC‐SOD, the major scavenger of reactive oxygen species in extracellular spaces, is decreased in humans with OA and in an animal model of OA. Our findings suggest that inadequate control of reactive oxygen species plays a role in the pathophysiology of OA.
Delayed gadolinium‐enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: Findings at different radiographic stages of disease and relationship to malalignment
Authors: Williams Ashley , Sharma Leena , McKenzie Charles A. , Prasad Pottumarthi V. , Burstein Deborah 
Published: October 2005

AbstractObjectiveDelayed gadolinium‐enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is used to examine the distribution of glycosaminoglycan in cartilage. This study sought to characterize dGEMRIC in the evaluation of knee osteoarthritis (OA) according to various radiographically determined disease parameters, and to examine the relationship between alignment of the knee joint and the lateral:medial dGEMRIC ratio.MethodsThirty‐one patients with knee OA underwent MRI with a dGEMRIC protocol at 1.5T. Semiflexed knee radiographs and full‐limb radiographs were also obtained for assessment of alignment.ResultsCompartments of the knee joint without joint space narrowing had a higher dGEMRIC index than those with any level of narrowing (mean 408 msec versus 365 msec; P = 0.001). In knees with 1 unnarrowed (spared) and 1 narrowed (diseased) compartment, the dGEMRIC index was greater in the spared versus the diseased compartment (mean 395 msec versus 369 msec; P = 0.001). In spared compartments, there was a trend toward a lower dGEMRIC index with increasing Kellgren/Lawrence (K/L) radiographic severity grade; the spared compartments of knees with a K/L grade 2 had a higher dGEMRIC index than those of knees with a K/L grade 4 (mean 425 msec versus 371 msec; P < 0.05). There was a range of dGEMRIC values in the spared compartments within a given K/L grade, demonstrating biochemical differentiation of disease in radiographically comparable compartments. Almost all compartments with narrowing had dGEMRIC indices of <400 msec. Valgus‐aligned knees tended to have lower dGEMRIC values laterally, and varus‐aligned knees tended to have lower dGEMRIC values medially; as a continuous variable, alignment correlated with the lateral:medial dGEMRIC ratio (Pearson's R = 0.43, P = 0.02).ConclusionThe biochemical information provided by dGEMRIC scans may augment radiography by improving the differentiation of disease status within a given radiographic grade, especially in early OA.
Effects of antirheumatic treatments on the prostaglandin E2 biosynthetic pathway
Authors: Korotkova Marina , Westman Marie , Gheorghe Karina R. , af Klint Erik , Trollmo Christina , Ulfgren Ann Kristin , Klareskog Lars , Jakobsson Per‐Johan 
Published: October 2005

AbstractObjectiveMicrosomal prostaglandin E synthase 1 (mPGES‐1) is up‐regulated in experimental arthritis and markedly expressed in synovial tissue biopsy samples from patients with rheumatoid arthritis (RA). This study was carried out to determine the effects of tumor necrosis factor (TNF) blockers and glucocorticoids on mPGES‐1 and cyclooxygenase (COX) expression, as well as biosynthesis of PGE2 in rheumatoid joints.MethodsIn vitro effects of TNF blockers and dexamethasone on the PGE2 biosynthetic pathway were examined in RA synovial fluid mononuclear cells (SFMCs) by flow cytometry. PGE2 levels in culture supernatants were measured by enzyme immunoassay. Expression of enzymes responsible for PGE2 synthesis ex vivo was evaluated by immunohistochemistry in synovial biopsy samples obtained from 18 patients before and after treatment with TNF blockers and from 16 patients before and after intraarticular treatment with glucocorticoids. Double immunofluorescence was performed using antibodies against mPGES‐1, COX‐1, COX‐2, and CD163.ResultsDouble immunofluorescence revealed that mPGES‐1 and COX‐2 were colocalized in SFMCs as well as in RA synovial tissue cells. The addition of either TNF blockers or dexamethasone suppressed lipopolysaccharide‐induced mPGES‐1 and COX‐2 expression in synovial fluid monocyte/macrophages in vitro and decreased the production of PGE2. Intraarticular treatment with glucocorticoids significantly reduced both mPGES‐1 and COX‐2 expression in arthritic synovial tissue ex vivo. The number of COX‐1–expressing cells in synovial tissue was also significantly decreased by glucocorticoid treatment. In contrast, neither mPGES‐1 nor COX‐2 expression in synovial tissue was significantly suppressed by anti‐TNF therapy.ConclusionThese data are the first to demonstrate the effects of antirheumatic treatments on mPGES‐1 expression in RA and suggest that the inhibition of PGE2 biosynthesis, preferably by targeting mPGES‐1, might complement anti‐TNF treatment for optimal antiinflammatory results in RA.
Influence of HLA–DR genes on the production of rheumatoid arthritis–specific autoantibodies to citrullinated fibrinogen
Authors: Auger Isabelle , Sebbag Mireille , Vincent Christian , Balandraud Nathalie , Guis Sandrine , Nogueira Leonor , Svensson Björn , Cantagrel Alain , Serre Guy , Roudier Jean 
Published: October 2005

AbstractObjectiveAntibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA‐associated HLA–DR alleles are associated with anti–citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA–DR molecules and their recognition by T cells.MethodsAntikeratin, antifilaggrin, and anti–citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA–DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire α‐ and β‐chains of fibrinogen) to purified HLA–DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls.ResultsHLA–DRB1*0404 was associated with anti–citrullinated fibrinogen in RA sera (P = 0.002). For the RA‐associated alleles HLA–DRB1*0401 and HLA–DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the α‐ and β‐chains of fibrinogen bound many HLA–DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA–DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls.ConclusionThe RA‐associated HLA–DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti–citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide–DR–T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.
A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium
Authors: Lally Frank , Smith Emily , Filer Andrew , Stone Michael A. , Shaw John S. , Nash Gerard B. , Buckley Christopher D. , Ed Rainger G. 
Published: October 2005

AbstractObjectiveRheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte–driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a disease‐specific manner to support neutrophil recruitment.MethodsHuman umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel‐plate, flow‐based adhesion assay and levels of neutrophil adhesion to ECs were measured.ResultsECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P‐selectin or E‐selectin reduced neutrophil adhesion, and an antibody against CD18 (the β2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin‐6 (IL‐6) was detectable in coculture supernatants, and both IL‐6 and neutrophil adhesion were reduced in a dose‐dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL‐6 also effectively abolished neutrophil adhesion.ConclusionSynovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL‐6–mediated crosstalk between fibroblasts and endothelial cells.
Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin‐like receptor KIR3DL2 in spondylarthritis
Authors: Chan A. T. , Kollnberger S. D. , Wedderburn L. R. , Bowness P. 
Published: October 2005

AbstractObjectiveThe spondylarthritides (SpA) are strongly associated with possession of HLA–B27. We hypothesized that the expression of abnormal forms of HLA–B27 in SpA may have a pathogenic role through interaction with cells bearing natural killer (NK) receptors, in particular, killer immunoglobulin‐like receptor (KIR) KIR3DL2, a receptor for HLA–B27 homodimer (B272). We therefore undertook the present study to determine the number and function of NK and T cells bearing KIR3DL2 in SpA.MethodsExpression of KIR3DL2 on NK and T cells was quantified in peripheral blood (PB) from 35 patients with SpA and 5 patients with juvenile enthesitis‐related arthritis (juvenile ERA); samples were compared with samples from healthy and rheumatoid arthritis (RA) controls. Paired synovial fluid (SF) was studied where available. Expression of other KIRs as well as activation, memory, and homing markers on KIR3DL2+ NK and T cells was quantified. NK cell survival was assessed using the apoptotic markers annexin V and 7‐aminoactinomycin D, and cytotoxicity by 51Cr release assay.ResultsIn SpA, an increased number of PB and SF NK and CD4+ T cells expressed the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells had an activated phenotype, and were protected from apoptosis by culture with a cell line expressing B272. SpA PB mononuclear NK cells from SpA patients showed greater cytotoxicity than those from controls.ConclusionKIR3DL2 expression on NK cells and CD4 lymphocytes is increased in SpA and ERA. These cells are activated and may have a pathogenic role.
Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus
Authors: Popovic Karin , Ek Monica , Espinosa Alexander , Padyukov Leonid , Harris Helena Erlandsson , Wahren‐Herlenius Marie , Nyberg Filippa 
Published: October 2005

AbstractObjectiveTo investigate the role of the novel cytokine high mobility group box chromosomal protein 1 (HMGB‐1) in the pathogenesis of cutaneous lupus erythematosus (CLE).MethodsPunch biopsy specimens of lesional and unaffected skin from 10 patients with CLE and 3 healthy control subjects were investigated. Immunohistochemical staining for HMGB‐1, tumor necrosis factor α (TNFα), and interleukin‐1β (IL‐1β) was performed on consecutive sections. Analysis of single‐nucleotide polymorphisms of −308 TNF was performed on DNA extracted from peripheral blood mononuclear cells.ResultsAn altered expression of HMGB‐1 was observed both in the epidermis and in the dermal infiltrates of lesional skin. Expression of HMGB‐1 in the epidermis and dermis was increased (P < 0.01 and P < 0.001, respectively, versus unaffected skin), and translocation to the cytoplasm as well as the extracellular presence of secreted HMGB‐1 were found. Increased levels of TNFα and IL‐1β were also observed in the dermal infiltrates of lesional skin (P < 0.01 and P < 0.05, respectively, versus unaffected skin). The carrier frequency of the −308A TNF polymorphism was 80% in patients with subacute CLE, but this was not related to higher expression of TNFα in biopsy specimens from the CLE group.ConclusionThe high amount of extracellular HMGB‐1 observed in skin lesions indicates that HMGB‐1 is involved in the inflammatory process of CLE. TNFα and IL‐1β may form a proinflammatory loop with HMGB‐1, since they can induce the release of each other. The extracellular HMGB‐1 observed by immunostaining of the epidermis indicates that keratinocytes may be an as yet unrecognized source of secreted HMGB‐1, underscoring the role of the target organ in the rheumatoid autoimmune inflammatory process.