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U Müller-Ladner

Publications and source records attributed to U Müller-Ladner.

At least 109 records · Page 6Linked to original sources
PubMed1998

Retroviral sequences in rheumatoid arthritis synovium.

There are several relationships between retroviruses and cellular transformation, as well as retroviruses being involved in the development of autoimmune diseases. Retroviruses have been discussed as etiologic agents modulating or triggering certain pathways in the pathogenesis of rheumatoid arthritis (RA). However, none of the currently known retroviruses has been identified as specific for RA. Due to the unique properties of retroviruses, distinct experimental approaches can be used to detect retroviral activity in cells and tissues. Current research in RA using state-of-the-art molecular biology techniques includes both the search for exogenous and endogenous retroviral gene sequences in synovium of patients with RA.

Animals↗
PubMed1998

Cysteine proteinase cathepsin K mRNA is expressed in synovium of patients with rheumatoid arthritis and is detected at sites of synovial bone destruction.

OBJECTIVE: Cysteine proteinases B and L have been shown to be involved in matrix degradation of joints in patients with rheumatoid arthritis (RA). Since the cysteine proteinase cathepsin K is assumed to play a pivotal role in osteoclast mediated bone resorption, we investigated the expression of cathepsin K in RA joints. METHODS: We studied 10 RA and 4 normal synovial specimens and 5 articular heads with RA lesions by in situ hybridization, applying specific riboprobes for cathepsin K, human collagen type I, and cathepsin B. Antibodies against monocyte/macrophage associated CD68 antigen were applied in immunohistochemistry. Reverse transcription-polymerase chain reaction (RT-PCR) and ribonuclease protection assay (RPA) were performed on 4 RA, 1 normal, and 1 immortalized normal fibroblast cultures. RESULTS: Cathepsin K mRNA expression was upregulated in RA synovium compared to normal synovium. Cathepsin K mRNA was expressed mainly by synovial fibroblasts. These data were confirmed by RT-PCR and RPA. In RA articular heads, cathepsin K mRNA was detected at sites where synovium attached and invaded underlying bone. The cells at these sites represented collagen type I and cathepsin B mRNA expressing fibroblasts as well as CD68+ macrophages and giant cells. In addition, a distinct expression of cathepsin K mRNA was also detected around lymphocytic infiltrates in RA synovium. CONCLUSION: The data indicate that cathepsin K is not only expressed by osteoclasts but also by synovial fibroblasts, and suggest that cathepsin K contributes to bone destruction mediated by RA synovial cells. The expression of cathepsin K around lymphocytic infiltrates suggests further to facilitate the movement of mononuclear cells through the perivascular interstitial matrix and thereby contribute to interstitial matrix turnover.

Adult↗
PubMed1997

Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective.

Rheumatoid arthritis (RA) is characterized by progressive destruction of synovial cartilage. In vitro, degradation of cartilage is stimulated by IL-1, a proinflammatory cytokine, which is released from RA synovial fibroblasts (RA-SF). To determine whether gene therapy using the gene encoding the naturally occurring inhibitor of IL-1, IL-1 receptor antagonist (IL-1Ra) is feasible, IL-1 Ra-transduced RA-SF were coimplanted with normal human cartilage in SCID mice. The IL-1 Ra-transduced RA-SF continued to secrete IL-1Ra over a 60-day period. Cartilage that was coimplanted with RA-SF transduced with a marker gene exhibited progressive, chondrocyte-mediated cartilage degradation, whereas no such degradation was observed in cartilage that was coimplanted with RA-SF transduced with IL-1 Ra. Thus, gene therapy using a retrovirus-based gene delivery system appears to be a feasible approach to effectively modifying the local synovial environment.

Animals↗
PubMed1997

Tenosynovial nodulosis in a patient infected with human T cell lymphotropic virus I.

We describe a 45-year-old man who presented with multiple nodules along the tendons of the scapular region, the elbows, wrists, forearms, thighs, and ankles. The patient was a carrier of human T cell lymphotropic virus I (HTLV-I), which was probably transmitted from his mother; his mother also had polyarthritis. Histopathologically, the nodules consisted of numerous, small, fibrinoid masses. The synovium adjacent to the tendon sheath was hyperplastic, with fibrinoid necrosis mimicking rheumatoid synovium. However, synovitis was not present inside the adjacent joint. HTLV-I proviral DNA was detected in the cells of the nodule, in tenosynovial cells, and in peripheral blood lymphocytes, but not in skin fibroblasts. In situ reverse transcription assay showed a high quantity of tax/rex messenger RNA in the proliferating lining cells. Based on these features, we classified this case as an atypical manifestation of HTLV-I-associated arthropathy associated with fibrinoid nodules resulting from chronic tenosynovitis.

Carrier State↗
PubMed1997

Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs.

The aim of this study was to determine prognostic markers for the outcome after 36 months of therapy with disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) and to study serial cytokine serum levels. During 36 months, 20 patients receiving DMARDs (nine patients gold sodium thiomalate and 11 patients methotrexate, no comparison undertaken) were followed for clinical and laboratory data. Investigation at baseline, 12, 24 and 36 months, included clinical, radiological and laboratory parameters such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and interleukin (IL)-1 beta, IL-6, tumor necrosis factor alpha (TNF-alpha), IL-1 receptor antagonist (IL-1RA) and IL-2. During the 3 yr of therapy, the patients showed significant clinical improvement and decline of ESR, CRP, and serum levels of IL-6 and IL-2. The decrease in IL-6 serum levels during the first year of therapy correlated significantly with the decrease, after 36 months, in the number of inflamed joints (r = 0.7608, P < 0.005), Lansbury index (r = 0.6642, P < 0.005) and morning stiffness (r = -0.6561, P < 0.005). In contrast to IL-6 or IL-2, TNF-alpha and IL-1RA did not vary significantly during the 3 yr of therapy. During 36 months of therapy, patients treated with DMARD showed significant improvement of clinical parameters and a trend for delayed progression of radiographic damage. The decrease in IL-6 concentration in serum during the first 12 months was the best prognostic marker for the clinical outcome after 36 months of DMARD therapy.

Aged↗
PubMed1997

Cellular pathways of joint destruction.

In the past year, evaluation of cellular pathways of rheumatoid synovial fibroblasts has been the focus of several laboratories investigating the molecular and cellular mechanisms operating in the pathogenesis of rheumatoid arthritis. Major topics that have been reported on include the adhesion and interaction of synovial fibroblasts with cartilaginous matrix and other synovial cells, intracellular signaling, and activation of gene transcription. Novel approaches to inhibiting cartilage destruction have also been described. In the latter case, thorough multicenter characterization of the interleukin-1/interleukin-1 receptor antagonist pathways resulted in the first gene therapy trials in animals and humans.

Arthritis, Rheumatoid↗
PubMed1997

Alternatively spliced CS-1 fibronectin isoform and its receptor VLA-4 in rheumatoid arthritis synovium.

OBJECTIVE: Extracellular matrix components and cell adhesion molecules play a role in the pathogenesis of rheumatoid arthritis (RA). Interaction between the integrin very late antigen-4 (VLA-4) and the connecting segment-1 (CS-1) fibronectin (FN) isoform may contribute to lymphocyte interaction in RA synovium. We examined both mRNA and protein expression of CS-1 FN in inflamed synovium, and VLA-4 expression in synovial tissue and on cultured fibroblast-like synoviocytes from patients with RA. METHODS: Snap frozen synovial tissue specimens of 10 patients with RA and 4 patients with osteoarthritis were examined for expression of CS-1 FN mRNA and protein by in situ hybridization and immunohistochemistry. VLA-4 expression of synovial fibroblasts and in synovial tissue was evaluated by flow cytometry and immunohistochemistry. RESULTS: CS-1 FN mRNA was detected in RA lining layer synoviocytes, around terminal vessels, and in endothelial cells. Double labeling revealed that most lining synoviocytes expressing CS-1 FN mRNA were CD68 negative. VLA-4 was found in RA synovial fibroblasts, sublining mononuclear cells, and lymphoid aggregates. CONCLUSION: Our findings suggest that expression of CS-1 FN may partially correlate with cell proliferation in the RA lining layer. VLA-4 was found in RA synovial lining, as well as on cultured synovial fibroblasts. Thus, VLA-4/CS-1 FN interaction may facilitate lymphocyte interaction and synovial proliferation in RA.

Anti-Allergic Agents↗
PubMed1996

Chronic complement C3 gene expression in the CNS of transgenic mice with astrocyte-targeted interleukin-6 expression.

Both cytokines and complement are thought to play significant, but poorly understood roles, in the pathogenesis of a variety of neurodegenerative diseases. In this study, we examined the expression of C3, the central component of complement, in the brains of transgenic mice with constitutive astrocyte expression of the proinflammatory cytokine, interleukin-6 (IL-6). Immunohistochemistry studies demonstrated elevated deposition of C3 in the brains of transgenic animals compared with normal animals. Northern blot analysis of mRNA from brain and other tissues demonstrated an age-related increase in C3 gene expression only in the brains of transgenic animals, indicative of local synthesis. In situ hybridization studies revealed coincidence between C3 and IL-6 transgene expression, as well as areas of neuronal and white matter damage observed in cerebellum and hind brain. Furthermore, C3 mRNA expression was observed in ependymal cells, perivascular mononuclear cells, endothelial cells, and scattered cells throughout the white matter and the brain stem. The overlap in C3 mRNA expression with areas of pathology suggests that complement may contribute to the inflammation and cellular injury observed in this model. The transgenic mice used in these studies provide a novel and valuable tool for examining the role of complement in central nervous system pathobiology.

Animals↗
PubMed1996

Spontaneous pneumothorax in a patient with systemic sclerosis.

A 28-year-old woman developed spontaneously a right- sided pneumothorax, the leading clinical symptom of an as yet undiagnosed systemic sclerosis. The diagnosis was confirmed by Raynaud's phenomenon, microstomia, arthralgia, distal oesophageal dysfunction and antinuclear antibodies. Initial treatment with pleural suction was followed by thoracoscopy and segmental pulmonary resection. Spontaneous pneumothorax is a rare complication in patients with systemic sclerosis, most likely caused by the rupture of subpleural cysts.

Adult↗
PubMed1996

A one-day double-labelling technique for tissue specimens: immunogold-silver staining for in situ hybridization combined with alkaline phosphatase-anti-alkaline phosphatase (APAAP) immunohistochemistry for antigens.

An improved technique is described that addresses the problems of sensitivity, specificity, the use of hazardous radioactive equipment and time consumption in immunohistochemical labelling and double labelling of in situ hybridization of tissue specimens. It consists of a two-step protocol in which digoxigenin-uridine triphosphate (UTP) labelled riboprobes in the in situ hybridization step are visualized by the immunogold-silver staining method, and double labelling of tissue antigens is achieved by the application of an alkaline phosphatase-anti-alkaline phosphatase staining step. We tested this protocol using snap-frozen tissue sections of synovial tissue from patients with rheumatoid arthritis. The target mRNA was detected by perforin or cathepsin D riboprobes, the double labelling was performed using anti-collagen type IV and alpha-smooth muscle actin antibodies. It is concluded that, in comparison with an established three- to four-day double-labelling protocol used in many laboratories, this one-day combination is currently the most rapid assay of reliable quality for double labelling of in situ hybridization products and tissue antigens.

Alkaline Phosphatase↗
PubMed1996

Enhanced expression of chemotactic receptors in multiple sclerosis lesions.

We have previously shown that astrocytes and microglia express the receptors for C5a, interleukin-8 (IL-8) and N-formyl-Met-Leu-Phe (FMLP) in vitro. The expression and function of chemotactic receptors in the central nervous system (CNS) is, however, largely unexplored. In this study, we examined tissue sections from normal human brain and active, chronic active and chronic silent multiple sclerosis (MS) lesions for the expression of the receptors for C5a, IL-8 and FMLP by immunohistochemistry. In normal brain tissue, the expression of all three receptors was seen at low levels on astrocytes and microglia. In contrast, expression for all three receptors was markedly elevated on foamy macrophages in the acute and chronic active MS lesions. In addition, fibrous astrocytes stained intensely for the C5a receptor in the chronic active disease. Receptor expression in the chronic silent lesion was low and similar to that seen in normal brain, with staining confined to a few hypertrophic astrocytes and foamy macrophages. These are the first studies to demonstrate expression of these receptors in the CNS and elevated receptor expression in inflammatory MS lesions. The data suggest that these chemotactic receptors may play a role in inflammatory responses in MS and possibly in other CNS diseases.

Acute Disease↗
PubMed1996

Molecular and cellular interactions in rheumatoid synovium.

There is growing evidence that distinct molecular and cellular interactions in the rheumatoid synovium result in a complex cascade of pathophysiologic events. These interactions finally lead to progressive joint destruction, in a way that is different from all other joint diseases. Keystones are inflammation, proliferation of synovial cells, and attachment and invasion of synovial fibroblasts (in)to adjacent cartilage and bone, mediated by continuous release of matrix-degrading enzymes. Advances in molecular biology have provided numerous new data on the rheumatoid arthritis interaction cascade. Major research topics involve the balance of proinflammatory and inhibitory cytokines, the role of adhesion molecules in attachment of synovial fibroblasts to cartilage, and the localization of various matrix-degrading enzymes in the synovial lining. The results of the research reviewed here also provide a basis for future therapies including gene therapy.

Cartilage↗
PubMed1996

Distinct patterns of immunoglobulin classes and IgG subclasses of autoantibodies in patients with inflammatory bowel disease.

OBJECTIVE: The pathophysiological significance of autoantibodies in inflammatory bowel diseases (IBD) is still unclear. To assess specific immunological abnormalities we examined the distribution and restriction of immunoglobulin classes and subclasses of anti-neutrophil cytoplasmic antibodies (ANCAs) in ulcerative colitis and of antibodies to pancreatic juice (APJs) in Crohn's disease. METHODS: We tested 62 sera of patients with ulcerative colitis and 184 sera of patients with Crohn's disease for their immunoglobulin class and IgG subclass distribution of ANCAs (in ulcerative colitis patients) and APJs (in Crohn's disease patients) by fluorescence isothiocyanate (FITC)-labelled anti-human antibodies in an immunofluorescence assay with human granulocytes or pancreas as substrate. Twenty-five patients with Wegener's granulomatosis were used for comparison. RESULTS: In ulcerative colitis ANCAs were found in 74% of the patients. They were predominantly of the IgG (96%) and IgA class (37%). In Crohn's disease APJs (present in 28% of the cases) were of the IgG (98%) and IgA class (71%). ANCAs in ulcerative colitis were of the IgG1 (73%) and IgG3 (5%) subclasses, APJs in Crohn's disease of the IgG1 (94%), IgG2 (20%) and IgG3 (2%) subclasses. The immunoglobulin class and IgG subclass distributions of ANCAs and APJs resembled the changes in total immunoglobulin classes and IgG subclasses in ulcerative colitis or Crohn's disease. CONCLUSION: The immunoglobulin classes and IgG subclasses of autoantibodies in ulcerative colitis and Crohn's disease differ from each other and from the distribution of autoantibodies in vasculitic diseases (Wegener's granulomatosis, microscopic vasculitis, systemic lupus erythematosus). These alterations reflect specific pathophysiological features of ulcerative colitis and Crohn's disease.

Adolescent↗
PubMed1996

Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts.

OBJECTIVE: There is evidence that proliferation of synovial fibroblasts and invasive growth in rheumatoid arthritis (RA) is due to impaired regulation of the cell cycle, i.e., the balance between proliferation and physiological cell death (apoptosis) We examined synovial tissues from patients with RA and osteoarthritis (OA) to determine the ultrastructural changes during apoptosis and the expression of the apoptosis regulating molecules Fas and Bcl-2 in synovial fibroblasts. METHODS: We examined synovial tissues obtained from patients with RA and OA by electron microscopy and immunoelectron microscopy to evaluate the characteristics of apoptosis in RA synovial fibroblasts as well as Fas and Bcl-2 antigen expression. RESULTS: Ultrastructurally, the majority of the RA synovial fibroblasts appeared transformed, and 3% of these were in different stages of apoptosis. In OA, no apoptotic cells could be observed. Apoptosis of synovial fibroblasts in RA showed a characteristic multistage pattern. In each of the distinguishable 4 stages, specific ultrastructural changes could be detected. The apoptotic synovial fibroblasts were mainly located in the deeper sublining layers of the synovium. Immunoelectron microscopy revealed that Fas antigen expression was limited to the first stage of apoptosis. Conversely, the synovial fibroblasts located in the synovial lining layer neither underwent apoptosis nor expressed Fas antigen. Several synovial lining cells expressed the cell death suppressor (anti-apoptosis) gene product Bcl-2. CONCLUSION: Apoptosis of fibroblasts in the RA synovial sublining is characterized by a distinct multistep ultrastructural pattern with a detectable initial Fas antigen expression; conversely, reduced apoptosis in the synovial lining associated with the expression of Bcl-2 results in extended life of matrix degrading synovial fibroblasts at the site of synovial invasion into cartilage and bone.

Adult↗
PubMed1996

Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice.

Rheumatoid arthritis (RA) has been thought to be largely a T-cell-mediated disease. To evaluate the role of T-cell-independent pathways in RA, we examined the interaction between isolated RA synovial fibroblasts and normal human cartilage engrafted into SCID mice in the absence of T cells and other human cells. The expression of cartilage-de grading enzymes and adhesion molecules was examined by immunohistochemistry and in situ hybridization techniques. The RA synovial fibroblasts invaded the cartilage and kept their transformed appearing cellular shape. They expressed VCAM-1 and produced the cathepsins L and B at the site of invasion. We conclude that RA synovial fibroblasts maintain their invasive and destructive behavior over longer periods of time in the absence of human T cells, indicating that T-cell-independent pathways play a significant role in rheumatoid joint destruction.

Animals↗