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ID PMID Title PublicationDate abstract
17962240 Exocrine function in primary Sjögren syndrome: natural course and prognostic factors. 2008 Jul OBJECTIVES: Few studies have addressed the natural course of, or prognostic factors for the salivary and lacrimal function in primary Sjögren syndrome (SS). Except for the early stages, glandular function has been seemingly stable, and SS A antigen (SSA) seropositivity and hypocomplementemia may predict a decline in the van Bijsterveld score. The aim of the present study was to assess the natural course of the exocrine function in a larger cohort based on the American-European consensus criteria for SS, and to address possible predictive factors for a declining exocrine function. METHODS: We performed a retrospective cohort study. A total of 141 patients were investigated with the Schirmer I test and unstimulated whole saliva (UWS). Historical data regarding these tests and focus score were collected from the files of 111 patients. Median time from diagnosis to follow-up investigation was 5.0 years. RESULTS: Median UWS was unchanged during follow-up. Median Schirmer I test improved from 5.0 to 7.0 mm/5 min (p<0.05). Present Schirmer I test was associated with historical high IgG and IgA, positive SSA and SS B antigen (SSB) tests and high focus score, and present UWS with historical low C3/C4. Logistic regression identified high focus scores (odds ratio (OR) = 1.343), and low UWS (OR = 0.692) as factors predicting a 30% or more worsening of the Schirmer I test. High focus scores (OR = 1.488) predicted a 30% or more worsening of the UWS. CONCLUSION: We confirmed previous studies showing a stable or slightly improved exocrine function over time. High focus scores and low UWS were identified as independent predictors of a worsened exocrine function.
17075840 Efficacy and mechanism of action of turmeric supplements in the treatment of experimental 2006 Nov OBJECTIVE: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA). METHODS: The composition of commercial turmeric dietary supplements was determined by high-performance liquid chromatography. A curcuminoid-containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. RESULTS: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-kappaB and the subsequent expression of NF-kappaB-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E(2), and periarticular osteoclast formation were inhibited by turmeric extract treatment. CONCLUSION: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.
17233227 Inflammatory conditions of the salivary glands. 2006 Dec Inflammatory conditions are the most common pathology to affect the salivary glands, of which sialolithiasis is the most frequent etiology. This article reviews the role of all imaging modalities in the management of inflammatory salivary disease. The technique for performing salivary gland ultrasound is described with some common pitfalls. The typical features of a comprehensive range of pathology including obstructive and infective sialadenitis, Sjogren's syndrome, sarcoidosis, HIV sialopathy, and their complications are described.
17180297 Unusual presentation of triple A syndrome mimicking Sjögren's syndrome. 2007 Oct Triple A syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. Sjögren's syndrome (SS) is a chronic inflammatory disorder manifested primarily by diminished lacrimal and salivary gland secretions, resulting in symptoms of dry eyes and dry mouth, the so-called "sicca complex". However, a variety of other manifestations also can occur, which can be termed "nonexocrine manifestations". One of the frequent nonexocrine manifestations is dysphagia. In this paper, we present an unusual form of Triple A disease mimicking Sjögren's syndrome, which leads to a challenging diagnosis.
16501068 Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. 2006 Jun Mitogen-activated protein kinase (MAPK) pathways are implicated in joint destruction in rheumatoid arthritis (RA) by modulating the production and functions of inflammatory cytokines. Although p38 MAPK (p38) participates in signaling cascades leading to osteolysis in arthritis, the mechanisms of its action in this process remain incompletely understood. Here, we found that the osteoclast (Ocl) precursors expressed p38alpha, but not p38beta, p38delta, and p38gamma isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-alpha was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409). To validate in vitro data, p38 role was further investigated in streptococcal cell wall (SCW)-induced arthritis in rats. We found that SCW-induced joint swelling and bone destruction were attenuated by SC-409. Mechanistically, the data show that SCW-stimulated DNA binding activity of the transcription factor myocyte-enhancing factor 2 C, which is downstream of p38, was inhibited by SC-409. In addition, SC-409 inhibited SCW-stimulated expression of numerous factors, including TNF-alpha, interleukin-1beta, and RANKL. Although c-Jun NH2-terminal kinase and NF-kappaB pathways were activated in vitro by RANKL and in vivo by SCW, SC-409 had no significant effect on these pathways. In conclusion, our data show that p38 modulates the production and signaling of cytokines, thus providing a mechanism of the bone-sparing effect of SC-409 in rat arthritis. These data present SC-409 as a novel potent p38 inhibitor and suggest that p38-based therapies may be beneficial in preventing bone loss associated with RA.
19068774 [Primary Sjögren's syndrome with lymphocytic interstitial pneumonia, autoimmune hemolytic 2008 Nov A 73-year-old woman was admitted to our hospital for examination of anemia, dry feeling of oral and eyes with chest abnormal shadow in October, 1999. Chest radiograph showed interstitial shadows difference and CT showed small nodular opacities in both lung fields. Laboratory examination showed direct Coombs test was positive, and the serum levels of indirect bilirubin and haptoglobin were elevated. Anti-SS-A antibody and anti-SS-B antibody were positive with hypergammaglobulinemia. The serum levels of SP-D and KL-6 were elevated. Lip biopsy showed atrophy and lymphocyte infiltration of the salivary glands. According to these findings, she was diagnosed as primary Sjögren's syndrome with autoimmune hemolytic anemia. In addition, bronchoscopic examination showed an endobronchial polyp in the right B8, and the biopsy specimen showed AL type amyloid deposits. In order to obtain pathological diagnosis of lung lesions, we performed lung biopsy by video-assisted thoracoscopic surgery. The biopsy specimen showed severe infiltration of lymphocytes and the plasma cells around peribronchiole with lymphoepithelial lesions, suggesting malignant lymphoma. However, immunohistochemistry did not show monoclonal profile and Southern blot hybridization assay demonstrated no rearrangement of JH gene. Lung lesions were diagnosed as lymphocytic interstitial pneumonia due to Sjögren's syndrome. Steroid therapy was performed and followed by improvement of anemia and pulmonary lesions. Malignant lymphoma has not been involved for eight years after a diagnosis.
18846009 Apoptosis and cell proliferation: the paradox of salivary glands in Sjögren's disease. 2008 Jul AIM: To assess apoptosis and proliferation in salivary glands of patients with primary Sjögren's syndrome. METHODS: Studies were performed in twenty four minor salivary glands from patients with primary Sjögren's syndrome and an equal number of controls. Apoptosis was studied by immunohistochemistry using monoclonal antibodies anti-Fas FasL and Caspase 3 and apoptotic features by TUNEL. Proliferation was assessed with monoclonal anti-PCNA and anti-Ki67 antibodies. RESULTS: All salivary glands from Sjögren's display apoptotic molecules along the epithelia of salivary ducts and in a smaller amount in acinar tissue. The presence of Caspase 3 Fas FasL was concordant with the expression of apoptosis by TUNEL. Proliferation markers were encountered in inflammatory emigrant cells but not in ductal epithelia nor in acini. Control biopsies poorly expressed apoptotic or proliferation markers. CONCLUSION: Present data suggests that the ductal epithelial and acinar cells of salivary glands from Sjögren's disease patients exhibit increased apoptosis. Proliferation was mainly observed in infiltrating lymphoid cells. Both events constitute a biological paradox related to the inflammatory process of salivary glands in Sjögren's disease.
18203513 [Successful treatment with prednisolone for autoimmune myelofibrosis accompanied with Sjö 2007 Dec A 66-year-old woman presented with anemia in January 2006. She was admitted to our Department in February, after laboratory data showed pancytopenia and bone marrow biopsy reticulin fibrosis. The results of the diagnostic work-up, which included the anti-SS-A antibody, anti-SS-B antibody positivity and salivary gland scintigraphy, Schirmer test and Rose Bengal test, supported the classification criteria of Sjögren syndrome. Due to secondary myelofibrosis accompanied by Sjögren syndrome, she was started on prednisolone (PSL) and recovered completely from the anemia and thrombocytopenia. After the PSL was tapered, a recent follow-up indicated that the peripheral blood had normalized with the PSL therapy. As a causal disease of autoimmune myelofibrosis in collagen disease, systemic lupus erythematosus occurs frequently. This patient is considered to be a rare case in whom secondary myelofibrosis was accompanied by Sjögren syndrome.
17992589 The role of epithelial cells in the pathogenesis of Sjögren's syndrome. 2007 Jun Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy that is characterized by periductal mononuclear cell infiltrates in the affected exocrine glands. Epithelial cells are thought to play an important pathogenetic role, as suggested by the occurrence of infiltrating lesions in various epithelial tissues (described as autoimmune epithelitis) as well as the increased epithelial expression of several inflammatory proteins in the histopathologic lesions of patients. In the recent decade, the application of long-term cultured nonneoplastic salivary gland epithelial cell (SGEC) lines has permitted the more explicit analysis of the role of these cells in SS pathophysiology. In such studies, cultured SGEC have been demonstrated to express constitutively or inducibly various molecules that are implicated in innate and acquired immune responses, a fact that underscores the inherent capacity of these epithelial cells to induce and promote chronic inflammatory reactions. Furthermore, the parallel analysis of SGEC lines obtained from SS patients and disease controls has revealed the significantly increased constitutive expression of several molecules in cells derived from SS patients. This fact strongly suggests the operation of intrinsic activation mechanisms in the epithelia of patients and further supports the active participation of epithelia in SS pathogenesis.
18050074 Tarsal tunnel syndrome in a patient on long-term peritoneal dialysis: case report. 2007 Oct Tarsal tunnel syndrome (TTS) is defined as the entrapment of the posterior tibial nerve in the tarsal tunnel of the ankle. The etiologies of tarsal tunnel syndrome are mainly the presence of a ganglion, osseous prominence with tarsal bone coalition, trauma, varicose veins, neurinoma, hypertrophy of the flexor retinaculum, or systemic disease (rheumatoid arthritis, ankylosing spondylitis). However, no specific cause can be identified in some cases. Patients with chronic renal failure tend to develop peripheral nerve entrapment and carpal tunnel syndrome is the best-known peripheral entrapment neuropathy among them. Contrary to carpal tunnel syndrome, tarsal tunnel syndrome is observed less frequently in chronic renal failure patients. The common presenting symptoms of TTS are paresthesias and/or pain in the plantar side of the foot. Motor symptoms are rarely detected. Diagnosis is made primarily by electroneuromyographic studies and physical examination. Surgery is the treatment of choice and the outcome is generally favourable. In this report, we present a patient with tarsal tunnel syndrome complicating peritoneal dialysis.
17223660 HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriati 2007 Jun BACKGROUND: Human leucocyte antigen (HLA) genes predict disease severity in psoriasis (HLA-Cw6) and rheumatoid arthritis (shared epitope (SE)), but the situation is unclear for psoriatic arthritis (PsA). AIM: To determine the association of the HLA-Cw6 and HLA-DRB1 gene with disease severity in a large UK cohort with PsA. METHODS: Genotyping of the HLA-Cw and HLA-DRB1 loci was undertaken in DNA samples from patients with PsA (n = 480). Stratification and regression analysis were used within the PsA cases to determine whether HLA-Cw6, HLA-DRB1 or the presence of the SE alleles predicted disease severity as measured by the Health Assessment Questionnaire score, the total number of damaged or involved joints adjusted for disease duration and disease-modifying antirheumatic treatments. RESULTS: HLA-Cw6 was found to be in linkage disequilibrium with HLA-DRB1*07 (r(2) = 0.46). Patients with PsA who carried both HLA-Cw6 and HLA-DRB1*07 had fewer damaged or involved joints (41% fewer damaged (95% CI 23% to 55%, p = 0.02) and 31% fewer involved joints (95% CI 16% to 44%, p<0.001)) compared with those who carried neither HLA-Cw6 nor HLA-DRB1*07 alleles. Those who carried either HLA-Cw6 or HLA-DRB1*07 alleles alone had no evidence of a reduction in joint involvement. The SE, HLA-DRB1*03 and HLA-DRB1*04 alleles did not predict severity using these outcome measures. CONCLUSION: Patients with PsA carrying both HLA-Cw6 and HLA-DRB1*07 alleles have a less severe course of arthritis. This suggests that a protective locus lies on a haplotype marked by these alleles. No association was detected with disease severity and SE status.
18032539 Five-year outcome of a primary-care-based inception cohort of patients with inflammatory p 2007 Dec OBJECTIVES: To establish whether patients with inflammatory arthritis plus psoriasis have a different outcome from those who do not have psoriasis. METHODS: Seventy-nine patients with inflammatory arthritis plus psoriasis were recruited by the Norfolk Arthritis Register (NOAR) in 1990-94 and followed for 5 yrs. Their outcome was compared with the remainder (n = 755) of the NOAR cohort. We then restricted the analysis to subjects who were rheumatoid factor (RF)-negative, and compared those with and without psoriasis. Outcomes studied included remission, deformed joint count, the presence and extent of erosive damage and physical function. RESULTS: Patients with psoriasis were younger, more likely to be male, less likely to be RF-positive and more likely to have been treated with disease-modifying drugs than patients without psoriasis. After adjustment for age, gender and treatment, the only differences between the psoriasis and non-psoriasis groups were in RF positivity (adjusted odds ratio 0.44; 95% CI 0.25, 0.78) and in the Larsen score in patients with erosions. CONCLUSIONS: Patients with inflammatory arthritis plus psoriasis have a similar outcome to other RF-negative patients with arthritis.
17218490 Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serol 2007 Apr BACKGROUND: As patients with B-cell lymphomas suffering from an underlying autoimmune condition undergoing therapy with the CD20 antibody rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) offer the unique possibility of monitoring effects of therapy on various rheumatologic parameters, we have evaluated serologic autoimmune markers and the clinical outcome of patients with autoimmune diseases (ADs) who received lymphoma treatment with R-CHOP during the course of their disease. PATIENTS AND METHODS: We have retrospectively analysed 13 patients with non-Hodgkin's lymphoma who concurrently suffered from ADs and were treated with the R-CHOP regimen. Subjective parameters along with rheumatoid factor (RF) and antinuclear antibodies (ANA) were serially measured. RESULTS: The median levels of RF were 901 IU/ml [inter-quartile-range (IQR) 189-2520] before and 75 IU/ml (IQR 45-644) after therapy (P = 0.028). The median levels of ANA were 800 (IQR 140-2560) before and 100 (40-1280) after therapy (P = 0.027). Ten (77%) patients showed clinical improvement of their autoimmune symptoms, two (15%) reported no difference and one (7%) patient with rheumatoid arthritis-related worsening symptoms during therapy with R-CHOP. The autoimmune-related symptoms recurred after a median time of 7 weeks (IQR 6-8) in seven patients. In terms of lymphoma response, 11 patients achieved a complete remission and two a partial remission. CONCLUSIONS: This analysis indicates that R-CHOP given for lymphoma treatment is also effective for therapy of concurrent rheumatoid diseases. Both rheumatoid parameters as well as clinical symptoms showed a significant decrease during treatment with this immunochemotherapy. The effects on the rheumatic diseases, however, seem to be of limited duration.
16169767 Some principles of the development of a clinical database/national register of selected in 2006 Mar According to the World Health Organisation, rheumatic diseases are likely to go on occupying a prominent place worldwide. As to US statistics, rheumatic diseases are currently the most frequent chronic disorders and leading cause of disability. The development of functional clinical database or rheumatic diseases represents an essential condition how to acquire necessary epidemiological and other information on disorders under study. In 1999-2003, Institute of Rheumatology in cooperation with EuroMISE have developed clinical database/national register of selected systemic inflammatory rheumatic diseases inclusive of bank of sera and DNA. Aims of this phase of the pilot research have been formulated into following relevant and time borders: to gather clinical, laboratory, genetic but also pharmaco- and socio-economic data in a representative sample of patients with systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, mixed connective tissue disease; rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriatic arthritis and reactive arthritis. The data about patients entering the register are differentiated according to the disease of the patient. However, many diseases have several data in common. Therefore, a simple common data structure for examination of all monitored diseases was chosen. In 2002, the preset number of over 2000 registered patients had been achieved with collaboration of 34 territorial and 20 institutional rheumatologists in the whole covering the majority of the Czech Republic. Some first acquired information inclusive comparison with German database is demonstrated.
17911645 Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T c 2007 Oct 15 Murine gammadelta T cell subsets, defined by their Vgamma chain usage, have been shown in various disease models to have distinct functional roles. In this study, we examined the responses of the two main peripheral gammadelta T cell subsets, Vgamma1(+) and Vgamma4(+) cells, during collagen-induced arthritis (CIA), a mouse model that shares many hallmarks with human rheumatoid arthritis. We found that whereas both subsets increased in number, only the Vgamma4(+) cells became activated. Surprisingly, these Vgamma4(+) cells appeared to be Ag selected, based on preferential Vgamma4/Vdelta4 pairing and very limited TCR junctions. Furthermore, in both the draining lymph node and the joints, the vast majority of the Vgamma4/Vdelta4(+) cells produced IL-17, a cytokine that appears to be key in the development of CIA. In fact, the number of IL-17-producing Vgamma4(+) gammadelta T cells in the draining lymph nodes was found to be equivalent to the number of CD4(+)alphabeta(+) Th-17 cells. When mice were depleted of Vgamma4(+) cells, clinical disease scores were significantly reduced and the incidence of disease was lowered. A decrease in total IgG and IgG2a anti-collagen Abs was also seen. These results suggest that Vgamma4/Vdelta4(+) gammadelta T cells exacerbate CIA through their production of IL-17.
16869003 Inhibition of angiogenesis by interleukin-4 gene therapy in rat adjuvant-induced arthritis 2006 Aug OBJECTIVE: Interleukin-4 (IL-4) can modulate neovascularization. In this study, we used a gene therapy approach to investigate the role of IL-4 in angiogenesis in rat adjuvant-induced arthritis (AIA), a model for rheumatoid arthritis. METHODS: Rats received an adenovirus producing IL-4 (AxCAIL-4), a control virus without insert, or control vehicle (phosphate buffered saline) intraarticularly before arthritis onset. At peak onset of arthritis, rats were killed. Vascularization was determined in the synovial tissue, and correlations with inflammation were assessed. Ankle homogenates were used in angiogenesis assays in vitro and in vivo, and protein levels of cytokines and growth factors were assessed by enzyme-linked immunosorbent assay. Synovial tissue expression of alphav integrins was determined by immunohistochemistry. RESULTS: IL-4 induced a reduction in synovial tissue vessel density, which was paralleled by a decrease in inflammation. AxCAIL-4 joint homogenates significantly (P < 0.05) inhibited both endothelial cell (EC) migration and tube formation in vitro. Similarly, AxCAIL-4 inhibited capillary sprouting in the rat aortic ring assay, and vessel growth in the in vivo Matrigel plug assay. The angiostatic effect occurred despite high levels of vascular endothelial growth factor (VEGF), and was associated with down-regulation of the proangiogenic cytokines IL-18, CXCL16, and CXCL5 and up-regulation of the angiogenesis inhibitor endostatin. Of interest, AxCAIL-4 also resulted in decreased EC expression of the alphav and beta3 integrin chains. CONCLUSION: In rat AIA, IL-4 reduces synovial tissue vascularization via angiostatic effects, mediates inhibition of angiogenesis via an association with altered pro- and antiangiogenic cytokines, and may inhibit VEGF-mediated angiogenesis and exert its angiostatic role in part via alphavbeta3 integrin. This knowledge of the specific angiostatic effects of IL-4 may help optimize target-oriented treatment of inflammatory arthritis.
19066215 Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals 2008 Dec 16 CTLA-4 (CD152) negatively regulates T cell activation signaling, and the cytoplasmic domain of CTLA-4 (ctCTLA-4) itself has the capacity to inhibit T cell activation in vitro and in vivo. In this study, the inhibitory mechanisms of the cell-permeable recombinant protein Hph-1-ctCTLA-4 on T cell activation and its ability to prevent collagen-induced arthritis were analyzed. Hph-1-ctCTLA-4 prevented human and mouse T cell activation and proliferation by inhibition of T cell receptor-proximal signaling and the arrest of the cell cycle. Furthermore, Hph-1-ctCTLA-4 protected human umbilical vein endothelial cells (HUVEC) from the human CTL allo-response. The incidence and severity of collagen-induced arthritis were significantly reduced and the erosion of cartilage and bone was effectively prevented by i.v. injection and transdermal administration of Hph-1-ctCTLA-4. Inflammatory cytokine production (IL-1beta, IL-6, TNF-alpha, IL-17A) and collagen-specific antibody levels were significantly reduced, and the numbers of activated T cells and infiltrating granulocytes were substantially decreased. These results demonstrate that systemic or transdermal application of a cell-permeable form of the cytoplasmic domain of CTLA-4 offers an effective therapeutic approach for autoimmune diseases such as rheumatoid arthritis.
18668540 The mouse mast cell-restricted tetramer-forming tryptases mouse mast cell protease 6 and m 2008 Aug OBJECTIVE: Increased numbers of mast cells (MCs) that express beta tryptases bound to heparin have been detected in the synovium of patients with rheumatoid arthritis (RA). The corresponding tryptases in mice are mouse MC protease 6 (mMCP-6) and mMCP-7. Although MCs have been implicated in RA and some animal models of arthritis, no direct evidence for a MC-restricted tryptase in the pathogenesis of inflammatory arthritis has been shown. We created transgenic mice that lack heparin and different combinations of mMCP-6 and mMCP-7, to evaluate the roles of MC-restricted tryptase-heparin complexes in an experimental model of arthritis. METHODS: The methylated bovine serum albumin/interleukin-1beta (mBSA/IL-1beta) experimental protocol was used to induce inflammatory monarthritis in different mouse strains. Mice were killed at the time of peak disease on day 7, and histochemical methods were used to assess joint pathology. RESULTS: Arthritis was induced in the knee joints of mBSA/IL-1beta-treated mMCP-6(+)/mMCP-7(-) and mMCP-6(-)/mMCP-7(+) C57BL/6 mice, and numerous activated MCs that had exocytosed the contents of their secretory granules were observed in the diseased mice. In contrast, arthritis was markedly reduced in heparin-deficient mice and in mMCP-6(-)/mMCP-7(-) C57BL/6 mice. CONCLUSION: MC-derived tryptase-heparin complexes play important roles in mBSA/IL-1beta-induced arthritis. Because mMCP-6 and mMCP-7 can compensate for each other in this disease model, the elimination of both tryptases is necessary to reveal the prominent roles of these serine proteases in joint inflammation and destruction. Our data suggest that the inhibition of MC-restricted tryptases could have therapeutic potential in the treatment of RA.
19001053 Modulation of xylosyltransferase I expression provides a mechanism regulating glycosaminog 2009 Mar Osteoarthritis and rheumatoid arthritis are characterized by loss of proteoglycans (PGs) and their glycosaminoglycan (GAG) chains that are essential for cartilage function. Here, we investigated the role of glycosyltransferases (GTs) responsible for PG-GAG chain assembly during joint cartilage destruction and repair processes. At various times after antigen-induced arthritis (AIA) and papain-induced cartilage repair in rats, PG synthesis and deposition, expression of GTs, and GAG chain composition were analyzed. Our data showed that expression of the GT xylosyltransferase I (XT-I) gene initiating PG-GAG chain synthesis was significantly reduced in AIA rat cartilage and was associated with a decrease in PG synthesis. Interestingly, interleukin-1beta, the main proinflammatory cytokine incriminated in joint diseases, down-regulated the XT-I gene expression with a concomitant decrease in PG synthesis in rat cartilage explants ex vivo. However, cartilage from papain-injected rat knees showed up-regulation of XT-I gene expression and increased PG synthesis at early stages of cartilage repair, a process associated with up-regulation of TGF-beta1 gene expression and mediated by p38 mitogen-activated protein kinase activation. Consistently, silencing of XT-I expression by intraarticular injection of XT-I shRNA in rat knees prevented cartilage repair by decreasing PG synthesis and content. These findings show that GTs play a key role in the loss of PG-GAGs in joint diseases and identify novel targets for stimulating cartilage repair.
16684368 Interleukin-15 and interferon-gamma participate in the cross-talk between natural killer a 2006 We have characterized the lymphocyte subset and the receptor molecules involved in inducing the secretion of TNF by monocytic cells in vitro. The TNF secreted by monocytic cells was measured when they were co-cultured with either resting or IL-15-stimulated lymphocytes, T cells, B cells or natural killer (NK) cells isolated from the peripheral blood of healthy subjects and from the synovial fluid from patients with inflammatory arthropathies. Co-culture with IL-15-activated peripheral blood or synovial fluid lymphocytes induced TNF production by monocytic cells within 24 hours, an effect that was mainly mediated by NK cells. In turn, monocytic cells induced CD69 expression and IFN-gamma production in NK cells, an effect that was mediated mainly by beta2 integrins and membrane-bound IL-15. Furthermore, IFN-gamma increased the production of membrane-bound IL-15 in monocytic cells. Blockade of beta2 integrins and membrane-bound IL-15 inhibited TNF production, whereas TNF synthesis increased in the presence of anti-CD48 and anti-CD244 (2B4) monoclonal antibodies. All these findings suggest that the cross-talk between NK cells and monocytes results in the sustained stimulation of TNF production. This phenomenon might be important in the pathogenesis of conditions such as rheumatoid arthritis in which the synthesis of TNF is enhanced.