Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes.

Fibroblast activation protein (FAP), as described so far, is a type II cell surface serine protease expressed by fibroblastic cells in areas of active tissue remodelling such as tumour stroma or healing wounds. We investigated the expression of FAP by fibroblast-like synoviocytes (FLSs) and compared the synovial expression pattern in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Synovial tissue from diseased joints of 20 patients, 10 patients with refractory RA and 10 patients with end-stage OA, was collected during routine surgery. As a result, FLSs from intensively inflamed synovial tissues of refractory RA expressed FAP at high density. Moreover, FAP expression was co-localised with matrix metalloproteinases (MMP-1 and MMP-13) and CD44 splice variants v3 and v7/8 known to play a major role in the concert of extracellular matrix degradation. The pattern of signals appeared to constitute a characteristic feature of FLSs involved in rheumatoid arthritic joint-destructive processes. These FAP-expressing FLSs with a phenotype of smooth muscle actin-positive myofibroblasts were located in the lining layer of the synovium and differ distinctly from Thy-1-expressing and non-proliferating fibroblasts of the articular matrix. The intensity of FAP-specific staining in synovial tissue from patients with RA was found to be different when compared with end-stage OA. Because expression of FAP by RA FLSs has not been described before, the findings of this study highlight a novel element in cartilage and bone destruction of arthritic joints. Moreover, the specific expression pattern qualifies FAP as a therapeutic target for inhibiting the destructive potential of fibroblast-like synovial cells.

Cytokine profile in serum and synovial fluid of arthritis patients with Chlamydia trachomatis infection.

Chlamydia trachomatis (Ct)-induced arthritis (CtIA) is characterized by persistent Ct infection, which stimulates secretion of cytokines in vitro. We therefore investigated whether CtIA patients have a unique cytokine profile in synovial fluid or serum in vivo. Because underlying Ct infection is overlooked in a high percentage of patients with initially diagnosed undifferentiated oligoarthritis (UOA), we examined whether determination of cytokines might also be of diagnostic relevance for this arthritis form. Matched serum and synovial fluid specimens from 26 patients with CtIA were analyzed and compared to those from 34 patients with UOA in whom Ct infection was excluded and those of nine patients with rheumatoid arthritis (RA). In 15 CtIA patients, Ct DNA from synovial fluid could be amplified by polymerase chain reaction. The following cytokine or cytokine antagonists were measured by enzyme-linked immunosorbent assay: interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-1 receptor antagonist, and soluble TNF receptor p75. No statistically significant differences in cytokine levels between patients with CtIA or the other arthritis forms were detected. Also, comparison between CtIA patients with (n = 17) and without Chlamydia DNA (n = 9) in synovial fluid revealed no significant differences for these cytokines. Cytokine levels in serum and synovial fluid were not different between CtIA, UOA without Ct infection, and RA patients. The intracellular presence of Ct was not associated with a specific profile of these cytokines in vivo.

Improvement of Erdheim-Chester disease in two patients by sequential treatment with vinblastine and mycophenolate mofetil.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' form of histiocytosis with a plethora of different clinical manifestations owing to multiple organ involvement. We report two patients who presented initially with different clinical symptoms. The presenting complaint of the first patient was bone pain, predominantly in the legs, whereas in the other patient the initial symptoms were related to obstruction of both ureters, as in idiopathic retroperitoneal fibrosis. Ultimately, ECD was diagnosed in both patients by the occurrence of both pathognomonic manifestations, the histologic presence of non-Langerhans' histiocytes in bone biopsies, and osteosclerotic lesions of the long bones. Because the extraosseous manifestations progressed and a single application of corticosteroids was ineffective, sequential treatment with vinblastine and mycophenolate mofetil, together with prednisolone, was started. At follow-up respectively 15 and 16 months after the start of treatment a beneficial effect was noted in both patients. These cases illustrate the clinical spectrum of ECD, detail the pathognomonic manifestations of this rare disease, emphasize the need to consider ECD as an uncommon but important differential diagnosis in patients with arthralgias or systemic fibrosis, and give the first evidence for a new treatment option.

Chlamydia trachomatis-infected macrophages induce apoptosis of activated T cells by secretion of tumor necrosis factor-alpha in vitro.

Chlamydia trachomatis-infected macrophages induce T cell apoptosis. This ability might promote intracellular survival of Chlamydia and perpetuate chronic chlamydial infection. The purpose of this study was to examine the molecular mechanisms by which C. trachomatis-infected macrophages induce T cell apoptosis. Monocytes and T cells were isolated from the peripheral blood of healthy donors. Macrophages were infected with C. trachomatis, and autologous T cells were stimulated by mitogen. After 6 days, both populations were cultured together using a two-chamber transwell membrane system to differentiate between mechanisms involving either cell-to-cell contact or secretion of apoptotic factors. Apoptotic T cells were identified by propidium iodide through-flow cytometry, and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured by enzyme-linked immunosorbent assay. Antagonists of TNF-alpha, the Fas (CD95) molecule, TNF-related apoptosis-inducing ligand (TRAIL), and catalase were added to differentiate between the pathways of apoptosis. C. trachomatis-infected macrophages significantly induced T cell apoptosis by cell-to-cell contact (mean +/- standard deviation, 30+/-4%; P<0.001) and by humoral mechanisms (mean +/- standard deviation, 22+/-3%, P<0.001). Humoral apoptosis was mediated by secretion of TNF-alpha from infected macrophages. Inhibition of secretory TNF-alpha by the monoclonal anti-TNF-alpha antibody adalimumab (D2E7) blocked T cell death in vitro. In contrast, T cell apoptosis mediated by cell-to-cell contact was not inhibited by the different anti-apoptotic reagents. In summary, TNF-alpha derived from infected macrophages is an important apoptosis factor for T cell apoptosis induced by C. trachomatis-infected cells.

Microbe-induced T cell apoptosis: subversion of the host defense system?

Cells of multicellular organisms are equipped with a self destruction program called apoptosis to ensure homeostasis of the organism. Contraction of the lymphocyte compartment following recovery from an infection is controlled by this mechanism. But apoptosis of lymphocytes might be an Achilles tendon accessible to microbes to subvert the immune system. Evidence is cumulating that microbes use this mechanism to destroy microbe-specific T cells. We present an overview of microbe-induced T cell apoptosis discussing the consequences for the pathogenesis of microbial infection. The conventional role of lymphocytes during infection is to impose apoptotic threat to infected cells, the subject of this review highlights the opposite, lymphocytes as targets of microbe-induced death.