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ID PMID Title PublicationDate abstract
17471579 Orbital blood flow velocities in patients with rheumatoid arthritis. 2007 Sep PURPOSE: To assess orbital blood flow changes in patients with rheumatoid arthritis using Doppler sonography. PATIENTS AND METHODS: The study comprised 35 patients who were diagnosed with RA and were treated at the Department of Physical Therapy and Rehabilitation at Duzce Medical School. A control group consisted of 35 healthy volunteers. Color Doppler imaging was used to measure peak systolic velocity (PSV) and end diastolic velocity (EDV), from which the resistance index (RI) was calculated in the ophthalmic artery (OA), central retinal artery (CRA), and posterior ciliary arteries (PCAs). RESULTS: In the OA, PSV, EDV, and RI were, respectively, 36.7 +/- 0.6 cm/sec, 9.7 +/- 0.2 cm/sec, and 0.73 in the control group versus 34.7 +/- 3.0 cm/sec, 9.1 +/- 1.1 cm/sec, and 0.74 in the patient group. In the CRA, they were, respectively, 11.8 +/- 1.7 cm/sec, 3.6 +/- 0.7 cm/sec, and 0.66 in the control group versus 11.1 +/- 1.7 cm/sec, 3.4 +/- 0.7 cm/sec, and 0.68 in the patient group. In the PCAs, they were, respectively, 13.2 +/- 1.2 cm/sec, 4.7 +/- 0.6 cm/sec, and 0.65 in the control group versus 12.4 +/- 1.2 cm/sec, 4.2 +/- 0.6 cm/sec, and 0.66 in the PCAs. PSV, EDV, and RI of the PCAs and OA and RI of the CRA were significantly different between patients and controls, whereas there was no difference in the serum levels of glucose, triglyceride, low-density lipoprotein cholesterol, and total cholesterol. In the patient group, there was a significant correlation between orbital blood flow and duration of disease. CONCLUSION: Ocular blood flow appears to be slightly lower in RA patients than in healthy controls, suggesting that RA is a systemic inflammatory disease that may also involve ocular vessels.
16501834 Malignant lymphoma in patients with systemic rheumatic disease (rheumatoid arthritis, syst 2006 Jan We conducted clinicopathologic and immunohistochemical analyses of the prevalence of Epstein-Barr virus (EBV) among 24 patients with malignant lymphoma complicating systemic rheumatic diseases. (SRD) These 24 patients included 17 with rheumatoid arthritis (RA), 3 with systemic lupus erythematosus (SLE), 2 with systemic sclerosis (SS), and 2 with dermatomyositis (DM). There were 2 men and 22 women ranging in age from 30 to 86 years (mean: 64 years). The interval between the onset of rheumatic disease and that of malignant lymphomas ranged from 3 months to 35 years (mean: 142 months). The use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in 15 patients. Among them, 5 patients received methotrexate (MTX) therapy. Malignant lymphomas were found at extranodal sites in 9 patients, and the disease was in the advanced stage in 17 patients. Histologic and immunohistochemical studies demonstrated that 18 cases (75%) were B-cell lymphoma (RA=12, SLE=2, SS=2, DM=2), 3 (12.5%) were peripheral T-cell lymphoma (RA=3), and 3 (12.5%) were classical Hodgkin lymphoma (RA=2, SLE=1). As in previous reports, there was an increased frequency of diffuse large B-cell lymphoma (50%) in the present series. Moreover, a majority of the diffuse large B-cell lymphomas exhibited activated B-cell phenotype. EBV-encoded small RNAs (Epstein-Barr early region [EBER]-) and/or LMP-1+tumor cells were identified in only 3 cases of classical Hodgkin lymphomas. Our findings suggested EBV-associated lymphoma comprised only a small fraction of all non-Hodgkin's lymphomas in the general SRD patient population.
18821692 Junctional adhesion molecule C mediates leukocyte adhesion to rheumatoid arthritis synoviu 2008 Oct OBJECTIVE: Leukocyte infiltration into the rheumatoid arthritis (RA) synovium is a multistep process in which leukocytes leave the bloodstream and invade the synovial tissue (ST). Leukocyte transendothelial migration and adhesion to RA ST requires adhesion molecules on the surface of endothelial cells and RA ST fibroblasts. This study was undertaken to investigate the role of junctional adhesion molecule C (JAM-C) in mediating leukocyte recruitment and retention in the RA joint. METHODS: Immunohistologic analysis was performed on RA, osteoarthritis (OA), and normal ST samples to quantify JAM-C expression. Fibroblast JAM-C expression was also analyzed using Western blotting, cell surface enzyme-linked immunosorbent assay, and immunofluorescence. To determine the role of JAM-C in leukocyte retention in the RA synovium, in vitro and in situ adhesion assays and RA ST fibroblast transmigration assays were performed. RESULTS: JAM-C was highly expressed by RA ST lining cells, and its expression was increased in OA ST and RA ST endothelial cells compared with normal ST endothelial cells. JAM-C was also expressed on the surface of OA ST and RA ST fibroblasts. Furthermore, we demonstrated that myeloid U937 cell adhesion to both OA ST and RA ST fibroblasts and to RA ST was dependent on JAM-C. U937 cell migration through an RA ST fibroblast monolayer was enhanced in the presence of neutralizing antibodies against JAM-C. CONCLUSION: Our results highlight the novel role of JAM-C in recruiting and retaining leukocytes in the RA synovium and suggest that targeting JAM-C may be important in combating inflammatory diseases such as RA.
17599748 Antigen-specific suppression of established arthritis in mice by dendritic cells deficient 2007 Jul OBJECTIVE: NF-kappaB inhibitors applied to animal models of rheumatoid arthritis (RA) demonstrate the important role of NF-kappaB in the production of mediators of inflammation in the joint and their antiinflammatory effects. Because NF-kappaB is involved in the differentiation, activation, and survival of almost all cells, its prolonged inhibition might have unwanted adverse effects. Therefore, we sought to apply NF-kappaB inhibitors more specifically, targeting dendritic cell (DC) differentiation, in order to influence the outcome of the autoimmune response, rather than to produce a broad antiinflammatory effect. We tested whether DCs treated with the NF-kappaB inhibitor BAY 11-7082 and exposed to arthritogenic antigen would suppress established arthritis in C57BL/6 mice. METHODS: Antigen-induced arthritis was generated in C57BL/6 mice by injection of methylated bovine serum albumin (mBSA). After mBSA challenge, mouse knee joints were injected with antigen-exposed BAY 11-7082-treated DCs or with soluble tumor necrosis factor receptor (sTNFR). Intraarticular injection of interleukin-1 (IL-1) was used to induce disease flare. RESULTS: Inflammation and erosion were suppressed in mice that received mBSA-exposed BAY 11-7082-treated DCs, but not in those that received keyhole limpet hemocyanin-exposed BAY 11-7082-treated DCs. Clinical improvement was dependent on IL-10 and was associated with antigen-specific suppression of the delayed-type hypersensitivity (DTH) reaction and switching of anti-mBSA antibody isotype from IgG2b to IgG1 and IgA. Suppression of the DTH reaction or arthritic disease was not impaired by concomitant administration of sTNFR. Suppression could be reversed with intraarticular administration of IL-1beta and could be restored by a second injection of mBSA-exposed BAY 11-7082-treated DCs. CONCLUSION: BAY 11-7082-treated DCs induce antigen-specific immune suppression in this model of inflammatory arthritis, even after full clinical expression of the disease. Such DCs have potential as antigen-specific therapy for autoimmune inflammatory arthritis, including RA.
17097659 Acceleration of atherosclerosis during the course of rheumatoid arthritis. 2007 Dec Patients with rheumatoid arthritis (RA) are predisposed to atherosclerosis and cardiovascular disease. This is thought to be caused in part, by exposure to chronic systemic inflammation during the course of the disease. We hypothesized that RA disease duration augments the effect of age on atherosclerosis. We measured the carotid artery intima-media thickness (IMT) in 631 consecutive RA patients. We ascertained age, sex and disease duration, established CV risk factors, RA clinical manifestations and markers of inflammation. We used multivariable regression to model IMT, with age as the independent variable. We then added RA duration quartile x age interaction terms to estimate the IMT-age relationship within RA duration strata. We found that the rate at which the IMT increased per unit of age steepened in proportion to the RA duration, from 0.154 mm/10 years among patients with RA for 7 years or less, to 0.295 mm/10 years among patients with RA for 20 years or more (P
16782732 Titration of infliximab treatment in rheumatoid arthritis patients based on response patte 2007 Jan OBJECTIVES: To observe the course of the disease activity in rheumatoid arthritis (RA) patients treated with the standard infliximab dosing regimen and to adjust treatment guided by the pattern of disease activity. METHODS: All RA patients starting infliximab treatment were included and observed for at least 37 weeks. At infusion 4 (week 14), European League Against Rheumatism response was assessed. In moderate responders the dose was unchanged and the disease activity was carefully observed. In case of stable disease activity, the dose was increased at infusion 5 (week 22). In case of a temporary response the interval was reduced. Paired t-testing was applied to the disease activity score with 28-joint counts (DAS28) at week 22 and study endpoint. RESULTS: A total of 76 patients were included. Response after 14 weeks: good 22 (29%) patients, moderate 26 (34%) patients, and non-response in 21 patients. Seven patients (9%) dropped out before week 14 due to adverse events (5) or patients' initiative (2). In patients with moderate response, the following disease course between infusion 4 and 5 was observed: improvement to good response 6, temporary response 6, stable disease activity 6, drop out 8. In moderate responders, interval reduction and dose increase resulted in a decrease in mean DAS28 from 5.1 to 3.6 [P = 0.005, mean interval 5.6 weeks, mean infliximab dose 4.8 mg/kg/8 week (endpoint)] and from 4.1 to 3.6 [P = 0.04, mean infliximab dose 7.3 mg/kg/8 week (endpoint)], respectively. CONCLUSION: Three different patterns of disease activity were observed in moderate responders after 14 weeks of infliximab treatment, i.e. further improvement, no change in disease activity or a temporary response. Both interval reduction and dose increase significantly reduced disease activity, however, with different mean infliximab dosages. In good responders the response was often sustained over follow-up, whereas non-responders showed modest or no improvement despite dose adjustments.
18713756 Association of the tumour necrosis factor-308 variant with differential response to anti-T 2008 Nov 15 Anti-tumour necrosis factor (TNF) agents have revolutionized the treatment of patients with rheumatoid arthritis (RA). These therapies are, however, expensive and 30% of patients fail to respond. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total n = 1050, etanercept n = 455, infliximab n = 450), we investigated whether genotypes of eight single nucleotide polymorphisms in the region containing the TNF gene were associated with response to anti-TNF therapy. Linear regression analyses adjusted for baseline 28 joint disease activity score (DAS28), baseline health assessment questionnaire score, gender and concurrent disease modifying anti-rheumatic drug treatment were used to assess association of these polymorphisms with treatment response, defined by change in DAS28 after 6 months. Analyses were performed in the entire cohort, and also stratified by anti-TNF agent. Association between DAS28 response and TNF-308 (rs1800629) genotype (P = 0.001) was detected across the whole cohort. After stratification by anti-TNF agent, the rare TNF-308AA genotype was associated with a significantly poorer response compared with TNF-308GG in etanercept (P = 0.001, n = 7) but not infliximab (P = 0.8, n = 17) treated patients. Conversely, the GA genotype at TNF-238 (rs361525) was associated with a poorer response to infliximab (P = 0.028, n = 40), but not etanercept (P = 0.6, n = 33). Owing to the small numbers of patients in some of the genotype groups examined, our data must be regarded as preliminary and will require replication in further large cohorts of anti-TNF-treated patients. If confirmed, our findings suggest the potential for genotype at these markers to aid selection of anti-TNF agent in patients with RA.
17068710 Outcome assessment of hemiarthroplasty of the shoulder: a 5-year follow-up with 4 evaluati 2006 Oct BACKGROUND: Outcome measurement of shoulder arthroplasty is not standardized. We compared 3 scores and 1 evaluation form. PATIENTS AND METHODS: We report on 35 hemiarthroplasties of the shoulder (32 cementless). Mean age of the patients was 62 (29-87) years. After a mean follow-up of 6 years (range 2-18 years) patients were evaluated with the Neer score, the Constant-Murley score, the score of the University of California in Los Angeles (UCLA) and the Society of Shoulder and Elbow Surgeons Basic Shoulder Evaluation Form. We also performed radiographic evaluation and sonographic evaluation of the rotator cuff. RESULTS: Although pain relief and patient satisfaction were promising, the overall results of the respective score showed low values (Neer score 56/100 points, Constant-Murley score 43/100 points, and UCLA score 19/35 points on average). INTERPRETATION: We recommend choice of a score with a high impact of pain and patient satisfaction. Furthermore, ability to cope with activities of daily living should be of more importance than strength.
17014719 PUMA-mediated apoptosis in fibroblast-like synoviocytes does not require p53. 2006 PUMA (p53-upregulated modulator of apoptosis) is a pro-apoptotic gene that can induce rapid cell death through a p53-dependent mechanism. However, the efficacy of PUMA gene therapy to induce synovial apoptosis in rheumatoid arthritis might have limited efficacy if p53 expression or function is deficient. To evaluate this issue, studies were performed to determine whether p53 is required for PUMA-mediated apoptosis in fibroblast-like synoviocytes (FLS). p53 protein was depleted or inhibited in human FLS by using p53 siRNA or a dominant-negative p53 protein. Wild-type and p53-/- murine FLS were also examined to evaluate whether p53 is required. p53-deficient or control FLS were transfected with PUMA cDNA or empty vector. p53 and p21 expression were then determined by Western blot analysis. Apoptosis was assayed by ELISA to measure histone release and caspase-3 activation, or by trypan blue dye exclusion to measure cell viability. Initial studies showed that p53 siRNA decreased p53 expression by more than 98% in human FLS. Loss of p53 increased the growth rate of cells and suppressed p21 expression. However, PUMA still induced apoptosis in control and p53-deficient FLS after PUMA cDNA transfection. Similar results were observed in p53-/- murine FLS or in human FLS transfected with a dominant-negative mutant p53 gene. These data suggest that PUMA-induced apoptosis in FLS does not require p53. Therefore, approaches to gene therapy that involve increasing PUMA expression could be an effective inducer of synoviocyte cell death in rheumatoid arthritis regardless of the p53 status in the synovium.
17425295 Quantitative structure-activity relationship of peptides binding to the class II major his 2007 May 3 Presentation of (glyco)peptides by the class II major histocompatibility complex molecule Aq to T cells plays a central role in collagen-induced arthritis, an animal model for the autoimmune disease rheumatoid arthritis. A peptide library was designed using statistical molecular design in amino acid space in which five positions in the minimal mouse collagen type II binding epitope CII260-267 were varied. A substantially reduced peptide library of 24 peptides with diverse and representative molecular characteristics was selected, synthesized, and evaluated for the binding strength to Aq. A multivariate QSAR model was established by correlating calculated descriptors, compressed to its principle properties, with the binding data using partial least-square regression. The model was successfully validated by an external test set. Interpretation of the model provided a molecular property binding motif for peptides interacting with Aq. The information may be useful in future research directed toward new treatments of rheumatoid arthritis.
18836787 Telescope allograft method to reconstitute the diaphysis in limb salvage surgery. 2009 Jul We propose a surgical technique for structural allograft reconstitution of the diaphysis of long bones, maximizing surface contact between host and allograft bone. This method, analogous to a telescope, overlaps the graft and host bone, theoretically increasing bone surface contact substantially. We report the outcome of 22 telescoped allograft junction sites in 19 patients who lacked sufficient host bone to accommodate a regular-length stemmed implant. This joint-sparing reconstruction preserved 15 of 16 adjacent joints at risk for replacement. Five patients needed additional surgery, but none for nonunion. The diaphyseal length could be reconstructed enough so that a short prosthesis (less than the critical 40% of total bone length) could be used. This biologic method to reconstruct major segments of the diaphysis is best suited for patients with quantitatively or qualitatively deficient residual bone stock after tumor resection or prosthetic revision. We believe it is an excellent technique for revision knee megaprostheses when there is a short remnant of proximal femur. LEVEL OF EVIDENCE: Level IV, therapeutic study.
17604285 Decreasing incidence of symptomatic gastrointestinal ulcers and ulcer complications in pat 2008 Feb BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause gastrointestinal (GI) ulcers and complications of ulcers. In 1997 in Amsterdam, the incidence of symptomatic GI events was 2.1% (95% CI 1.0-3.1) in patients with rheumatoid arthritis (RA). We conducted a new prospective, observational study on the symptomatic GI events in our outpatient clinics, and compared the data to a previous study conducted by our group. Over the same time period, a decline of GI events over the last decade was reported for US patients. METHODS: In 2003, three questionnaires were sent to all RA patients in Amsterdam at 4-month intervals, addressing medication use, dyspepsia, and symptomatic GI events in the previous 4 months. RESULTS: The incidence of GI events in high-risk patients, defined as age >or=60 and/or history of GI event) using NSAIDs or cyclo-oxygenase 2 specific inhibitors (COXIBs) was 1.2% (95% CI 0.2-2.3), which appears to be substantially lower than the 2.1% observed in 1997; however this difference did not reach statistical significance (p = 0.3). In 64% (95% CI 61-68) of the high-risk patients, acid-suppressive drugs (ie, proton pump inhibitors, prostaglandin analogues or high dose H2 antagonists) were used. In 1997 this percentage was significantly lower at 49% (45-52; p<0.001). The compliance to the Dutch guidelines for prevention of NSAID-related gastropathy was almost 75%, with 64% of the patients using acid-suppressive drugs and 11% using COXIBs. CONCLUSION: The present study reveals a decline of NSAID-induced gastrointestinal events, which is similar to the results observed in the US. This is most likely due to a more strict adherence to guidelines for prevention of NSAID gastropathy, and better treatment of rheumatoid arthritis.
17981712 Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. 2008 Jan 1 CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) activity that is expressed on numerous cell types and has a multitude of biological functions. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell (APC)-T-cell interaction. In this paper, we will review emerging data on CD26-mediated T-cell costimulation, suggesting that CD26 may be an appropriate therapeutic target for the treatment of immune disorders. However, the identity of its putative natural ligand had not yet been clearly elucidated. Recently, using protein engineering and proteomic approach, we have recently characterized the putative costimulatory ligand for CD26 in T-cells and the proximal signaling events directly associated with the cytoplasmic region of CD26 in CD26-associated T-cell costimulation, processes that are independent of the CD28 costimulatory pathway. Our work therefore presents novel findings that contribute to the area of T-cell costimulation and signal transduction.
17312988 Pathogenesis and evolution of carpal instability: imaging and topography. 2006 Dec Carpal instability is a biomechanical alteration with a multiple pathogenesis which, if not identified and treated in time, leads to gradual articular collapse. Traumatism is known to be one of the main causes of carpal instability, while deposits of microcrystals caused by metabolic (chondrocalcinosis and gout) and congenital (ulna minus variance) diseases are less frequently involved in the pathogenesis. In forms secondary to traumatism, the trauma causes ligamentous injuries that lead to misalignments of the joint surfaces, or badly healed fractures with consequent articular incongruency. In both situations, an alteration of carpal kinematics is generated and, if normal carpal biomechanics are not restored, this alteration leads, over the course of time, to degenerative alterations of the cartilage, followed by chondral erosions and to the exposure of the bone. We present the etiology, topography and consequences of carpal instability, discussing the diagnostic procedure, which always begins with a conventional X-ray examination, followed by a CT and/or an MRI with an intra-articular injection of contrast medium as the gold standard for a correct evaluation. Our aim is to present and compare the different patterns of carpal instability observed in our Radiology Institute with those found in literature.
16951705 Granulocyte colony-stimulating factor and neutrophils--forgotten mediators of inflammatory 2006 Sep Recent studies have highlighted the functional capacity of neutrophils as powerful mediators of tissue inflammation. Granule-packaged proteases and reactive oxygen intermediates, which are important for intracellular digestion during phagocytosis, are released from neutrophils during inflammation. In the extracellular environment, neutrophil-derived proteases can cause local tissue damage, but also regulate the activity of cytokines, cytokine receptors and chemokines. Neutrophils can themselves produce an array of inflammatory mediators, including cytokines, chemokines and complement; these cells also express Fc receptors, which can bind and possibly transport immune complexes into the extravascular compartment, as well as activating neutrophils at opsonised surfaces. Blood-borne neutrophils interact with, and then exit through, the endothelium of blood vessels, after which these cells die and must be removed safely. The balance between neutrophil survival and clearance is crucial to the resolution of inflammation. A major regulator of neutrophil production and survival is the cytokine granulocyte colony-stimulating factor (G-CSF). Treatment with G-CSF can exacerbate underlying inflammatory diseases in humans and mice, and G-CSF deficiency is profoundly protective against collagen-induced arthritis in mice. These findings implicate G-CSF as an important proinflammatory cytokine. This article discusses the roles of neutrophils and G-CSF during chronic inflammatory diseases.
17426065 The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controll 2007 Nov BACKGROUND: Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor alpha (TNFalpha) showed high response percentages in the groups treated with active drugs. OBJECTIVE: To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments. METHODS: First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility. RESULTS: In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34-79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons. CONCLUSION: The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNF-blocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.
18161003 Leflunomide-induced lung injury that developed after its withdrawal, coinciding with perip 2008 A 60-year-old rheumatoid arthritis (RA) female with lung fibrosis was treated with leflunomide (LEF) for only 12 days, and responded well. Twenty-five days after the withdrawal of the drug, she had fever, dyspnea, and an elevated serum C-reactive protein level. Chest CT revealed ground-glass opacities (GGOs) and consolidations forming a mosaic pattern, in lung fields including the upper, anterior and central areas, and honeycomb patterns in the lung bases and backs. The level of plasma A771726, an active metabolite of LEF, was still as high as that usually noted under LEF therapy. After pulsed steroid and cholestyramine administration, A771726 was depleted and she recovered. The peripheral blood lymphocyte count that had been approximately 1,000/microL, decreased to 220/microL just at the onset of lung injury, and rapidly and steadily returned to the preinjury level preceding recovery from the injury. Serum albumin level decreased in association with lung injury, and gradually returned to the preinjury level. Special caution is necessary when prescribing leflunomide to elderly patients with preexisting interstitial lung disease, and remains necessary until at least 1 month after its withdrawal.
18576331 Treatment of collagen-induced arthritis with an anti-osteopontin monoclonal antibody throu 2008 Jul OBJECTIVE: To test the effects of a novel monoclonal antibody (mAb) against human osteopontin (OPN) in the prevention and treatment of collagen-induced arthritis (CIA) and to elucidate the underlying mechanisms of these effects. METHODS: DBA/1J mice immunized with type II collagen to induce CIA were monitored to assess the effects of anti-OPN mAb on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. The effects of anti-OPN mAb on survival of activated T cells from arthritic mice and from the synovial fluid of patients with rheumatoid arthritis (RA) were determined by TUNEL assay or annexin V assay. The levels of apoptosis-related proteins (Bim, Bax, and Bcl-2) and NF-kappaB were detected by immunoblot analysis. RESULTS: One anti-OPN mAb, 23C3, was effective in inhibiting the development of CIA and even reversing established disease in DBA/1J mice. Monoclonal antibody 23C3 reduced the levels of serum type II collagen-specific autoantibodies and proinflammatory cytokines, and suppressed T cell recall responses to type II collagen. Mechanistic studies demonstrated that OPN prevented the death of type II collagen-activated murine T cells and synovial T cells from RA patients. Monoclonal antibody 23C3 promoted apoptosis of the activated T cells, particularly CD4+ T cells, by inhibiting activation of NF-kappaB and by altering the balance among the proapoptotic proteins Bim and Bax and the antiapoptotic protein Bcl-2. Screening of a phage display peptide library led to identification of the epitope ATWLNPDPSQKQ as being recognized by this novel antibody. CONCLUSION: Because of its ability to effectively promote apoptosis of activated T cells, mAb 23C3 may be a novel therapeutic agent for the treatment of RA.
17907194 Opsonization of late apoptotic cells by systemic lupus erythematosus autoantibodies inhibi 2007 Oct OBJECTIVE: Decreased clearance of apoptotic cells is suggested to be a major pathogenic factor in systemic lupus erythematosus (SLE). The aim of this study was to investigate whether the binding of SLE autoantibodies to apoptotic cells influences the phagocytosis of these cells by macrophages. METHODS: Apoptosis was induced in a human T cell line (Jurkat) and a keratinocyte cell line (HaCaT) by ultraviolet B irradiation. Binding of purified IgG from 26 SLE patients and 15 healthy controls to apoptotic cells was assessed by flow cytometry and Western blotting. Phagocytosis of IgG-opsonized apoptotic cells by monocyte-derived macrophages was assessed by light microscopy. Similar experiments were performed with a monoclonal antibody against SSA/Ro and IgG fractions from 5 patients with Sjögren's syndrome (SS) and 5 patients with rheumatoid arthritis (RA). RESULTS: IgG fractions from all 26 SLE patients bound to late apoptotic, but not early apoptotic, cells. IgG fractions isolated from SLE patients with different autoantibody profiles showed comparable levels of binding. IgG fractions from healthy controls did not bind. Opsonization of apoptotic cells with IgG fractions from SLE patients resulted in a significant inhibition of phagocytosis as compared with healthy control IgG fractions. A monoclonal antibody directed against SSA/Ro and IgG isolated from 5 antinuclear antibody (ANA)-positive patients with SS were also able to elicit these effects, whereas IgG from 5 ANA-negative patients with RA did not. The inhibitory effect of patient IgG was abolished by blocking either the Fcgamma receptors (FcgammaR) or the constant region of IgG, using a specific Fc-blocking peptide. CONCLUSION: Autoantibodies from SLE patients are able to opsonize apoptotic cells and inhibit their uptake by macrophages via an FcgammaR-dependent mechanism.
18157139 Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fus 2008 Jan IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH and observed in IL-17A-related diseases. Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.