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U Müller-Ladner

Publications and source records attributed to U Müller-Ladner.

122 records · Page 7Linked to original sources
PubMed1995

Demonstration of granzyme A and perforin messenger RNA in the synovium of patients with rheumatoid arthritis.

OBJECTIVE: To examine the gene expression of 2 highly specific markers of cytotoxic T lymphocyte (CTL) activation, the serine protease granzyme A and the pore-forming protein perforin, in synovial tissue of patients with rheumatoid arthritis (RA), and to compare the findings with those in osteoarthritis (OA) synovial tissue. METHODS: Snap-frozen synovial tissue specimens from 9 patients with RA and 5 patients with OA were examined. The number of CTL that expressed granzyme A or perforin messenger RNA was determined by in situ hybridization using nonradioactive riboprobes for granzyme A and perforin, and by a novel in situ reverse transcriptase technique. The signals were visualized by an immunogold-silver immunohistochemistry technique and compared with immunohistochemical labeling of T and B cells. Additional double-labeling was achieved using anti-type IV collagen, anti-macrophage (anti-CD68), anti-T lymphocyte (anti-CD45RO), anti-B lymphocyte (anti-CD20), and anti-natural killer cell (anti-CD56) antibodies in an alkaline phosphatase-anti-alkaline phosphatase assay. RESULTS: Granzyme A and perforin messenger RNA (mRNA) was observed in CTL in synovial specimens from all of the RA patients, whereas in specimens from OA patients only a few, single cells with a positive mRNA signal for these molecules could be detected. In the RA specimens, the number of lymphocytes showing a positive mRNA signal for granzyme A or perforin varied from 10% to 50%, reflecting the recent findings of other investigators studying synovial fluid. CONCLUSION: Our results demonstrate that gene expression of at least 2 CTL products, granzyme A and perforin, is up-regulated in the synovium of patients with RA compared with that in the synovium of patients with OA. These molecules presumably play an important role not only in lymphocyte-mediated cytotoxicity, but also in facilitating the migration of blood-borne mononuclear cells through the vascular basement membrane into the rheumatoid synovium.

Adult↗
PubMed1995

Progressive joint destruction in a human immunodeficiency virus-infected patient with rheumatoid arthritis.

This article reports the case of a 63-year-old patient with rheumatoid arthritis (RA) whose symptoms of RA improved after the occurrence of a secondary human immunodeficiency virus (HIV) infection; however, the HIV infection did not affect the histologic parameters of joint destruction to the same extent as it did the clinical symptoms. Histologic and immunohistologic joint examinations of this patient revealed an ongoing production of cartilage- and bone-degrading enzymes by macrophages and fibroblasts, without the presence of T cells. These findings demonstrate that progressive joint destruction in RA can occur in the absence of T cells. Moreover, our results support the hypothesis that both T cell-dependent and T cell-independent pathways play a significant role in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1995

T cell-independent cellular pathways of rheumatoid joint destruction.

An appreciation of the role of T cell-independent pathways in the pathogenesis of rheumatoid arthritis (RA) has led to significant advances. New approaches have included the identification of novel cytokines and growth factors and characterization of the recently defined chemokines. Greater insight has been achieved with regard to prostaglandin pathways and the role of the synovial matrix and vasculature. The synovial matrix contributes to cell regulation in RA to a greater extent than previously believed, and the vasculature of the synovium must now be regarded as an active participant in the regulation of cell growth. The most exciting development, however, is the recognition of the involvement of oncogenes and apoptosis pathways in the dysregulation of the synovial cell cycle, which presumably causes the continuous synovial growth that is characteristic of RA.

Apoptosis↗
PubMed1995

Expression of proteolytic cathepsins B, D, and L in periodontal gingival fibroblasts and tissues.

BACKGROUND: A major feature of gingivitis and periodontitis is the destruction of the collagenous matrix of the surrounding connective tissue. The hypothesis that proteolytic enzymes release from cells adjacent to the site of destruction was recently supported by the presence of increased levels of cathepsin B, D, and L in the gingival crevicular fluid of patients suffering from periodontal disease (PD). EXPERIMENTAL DESIGN: We studied the expression of mRNA of cathepsins B,D, and L in early passaged, adherent gingival fibroblasts of patients with chronic adult PD. In addition, we examined the presence of cathepsin D and L mRNA-expressing cells in periodontal tissue specimen by in situ hybridization, and we localized the respective enzymes by immunohistochemistry. RESULTS: Strong gene expression of the three cathepsin types could be detected by dot hybridization in all PD-derived gingival cells. Immunohistochemical distribution of cathepsins and mRNA for cathepsin D and L could be demonstrated mainly in PD tissue specimen, largely in the area in between the epithelium and the adjacent subepithelial connective tissue. Examination of the cell types revealed multiple macrophage- and fibroblast-shaped cells expressing positive staining for cathepsins. CONCLUSIONS: The present data support the the concept that cathepsins play a major role in tissue destruction and may represent a target for therapeutic interventions.

Adult↗
PubMed1995

Oncogenes in rheumatoid arthritis.

The evolving knowledge of the actions and interactions of (proto)oncogenes in cancer has deeply influenced the understanding of other nonmalignant diseases. In RA, the longstanding pathohistologic evidence of transformed-appearing synovial cells at the site of bone and cartilage attachment and joint destruction can now be explained in terms of alterations of cell regulation, cell cycle, and apoptotically triggered cell death. The detection of upregulated oncogenes and their gene products at these sites supported the hypothesis of an aberrant synovial cell type invading the joint. Interestingly, there are hints that this transformation of synovial cells may require more than one activated oncogene. A model was introduced by Carson and Ribero in 1993. In this model, a primary stimulus affects the cell and leads to the enhanced transcription of an oncogene (i.e., c-myc). A second stimulus activates other oncogenes and determines if this cell (i.e., a synovial fibroblast) proliferates (marked by the presence of bcl-2 mRNA) or undergoes apoptosis (marked by fas mRNA and Fas expression at the cell surface). This co-upregulation might explain why some investigators could not detect a significant upregulation of oncogenes in cultured synovial fibroblasts devoid of their normal milieu. Based on the results of the specific activity of Fas and perforin and recent data from our laboratory, we have modified Carson's model to include these data. As there exists an established retroviral model in which the tax sequence of the HTLV retrovirus initiates central oncogene transcription similar to those activated in RA, the retroviral particles, which do not resemble any other known retrovirus but are detectable in the synovial fluid, might well be an important stimulus in the pathogenesis of RA. To simplify the puzzling events of oncogene interactions in RA, we have summarized the data and propose that an oncogene network acts as a pathogenic mechanism in the synoviocytes of the rheumatoid joint. Similar to the "cytokine network" regulating the T-cell-dependent pathway, the "oncogene network" is presumably the major T-cell-independent pathway in RA (Fig. 4).

Apoptosis↗
PubMed1993

Current therapy of systemic sclerosis (scleroderma).

Treatment of systemic sclerosis (scleroderma) presents a challenge to both the patient and the physician. Established approaches include long-term physiotherapy, disease-modifying agents such as D-penicillamine, and treatment of organ involvement. These efforts are often unsatisfactory since the results are poor. However, recent advances include treatment of Raynaud's phenomenon (plasmapheresis, stanozolol, and prostacyclin analogues), scleroderma renal crisis (angiotensin-converting enzyme inhibitors), and gastric hypomotility (cisapride). This article covers the current approaches to the disease-modifying therapy including those related to the function of collagen-producing fibroblasts, vascular alterations, and the cellular and humoral immune system, as well as treatment of involved organs.

Acute Kidney Injury↗
PubMed1992

[Neonatal lupus erythematosus as an example of passively acquired autoimmunity].

Neonatal lupus erythematosus is a typical example of passively acquired autoimmune disease. Congenital heart block is the main complication caused by transplacentally transferred maternal IgG antibodies directed against SS-A- or SS-B-antigen. While the transient lupus dermatitis occurs post partum and is often triggered by UV-light exposition, the irreversible cardial damage takes place between the 18. and 24, week of pregnancy. During this period 52-kD-SS-A- and 48-kD-SS-B-antigen are expressed in the fetal cardial tissue. The autoimmune reaction leads to an irreversible fibrotic destruction of the atrioventricular node. The resulting AV block and an antibody-induced perimyocarditis support the development of fetal bradyarrhythmia and hydrops. The very early diagnosis of a fetal heart block in bradycardiac fetus by echocardiography is essential for a consecutive therapy with steroids. By a reduction of the maternal antibodies an improvement of cardial symptoms in the fetus may be achieved in cases with fetal hydrops. Pregnant women at high risk with known connective tissue disease, previous children with congenital heart block, high titers of SS-A-/SS-B-antibodies and immunogenetic predisposition (HLA-DR3) have to be monitored intensively because of the possibility of a prophylaxis with dexamethasone and, in some selected cases, plasmapheresis.

Female↗
PubMedDate not supplied

The SCID mouse--a novel experimental model for gene therapy in human rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by a progressive destruction of joints accompanied by synovial hyperplasia, inflammation and autoimmune phenomena. RA is a common disease, but current animal models resemble human RA only to a limited extent. As recent experimental approaches support the concept that T-cell-independent pathways may play a major role in RA, we developed a severe combined immunodeficient (SCID) mouse model to study the molecular and cellular interaction between RA synovium and cartilage. Both RA synovium as well as isolated RA synovial fibroblasts were able to invade and degrade normal human cartilage when coimplanted under the renal capsule of the SCID mice. Subsequently, we used this model to study the effects of retrovirus-based gene transfer of potentially inhibitory molecules into human RA synovial fibroblasts. Overexpression of interleukin (IL)-1 receptor antagonist reduced perichondrocytic cartilage degradation, but did not affect the invasiveness of RA synovial fibroblasts. Overexpression of tumor necrosis factor (TNF)-alpha receptor p55 revealed only a marginal effect. However, overexpression of IL-10 showed a most remarkable inhibition of cartilage destruction mediated by synovial fibroblasts. The SCID mouse model is a most useful tool not only to study the molecular basis of cartilage destruction, but also to evaluate novel approaches of gene therapy.

Journal Article↗
PubMedDate not supplied

[Chronic recurrent polychondritis].

Relapsing polychondritis (RP) is a recurrent, chronic und rare disease of unknown etiology, characterized by inflammation of cartilaginous structures of the ears, nose, respiratory tract and joints. The association with HLA-DR4 and the occurrence of antibodies to type-II collagen and other autoantibodies suggest that an immunologic mechanism is involved in its pathogenesis. In about 30% of occurrences RP is associated with other rheumatic or autoimmune diseases. Ocular inflammation, involvement of the cardiovascular system, skin, central nervous system and audiovestibular organ are most probably caused by vasculitis. The course of RP is variable. Severity and outcome primarily depend on the occurrence of associated autoimmune diseases and vasculitis. According to the activity and systemic manifestations, medical treatment includes nonsteroidal antiinflammatory drugs, corticosteroids and cytotoxic agents.

Autoantibodies↗