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Biomedical subjects

M Aringer

Publications and source records attributed to M Aringer.

At least 19 recordsLinked to original sources
PubMed2003

Functional and molecular aspects of transient T cell unresponsiveness: role of selective interleukin-2 deficiency.

Defects of T cell (Tc) proliferation have been demonstrated in several autoimmune diseases. Detailed mechanisms governing activation and proliferation of Tc are still not completely known. Here we show that under certain conditions human peripheral blood lymphocytes, once activated by anti-CD3, fail to respond to a subsequent restimulation via the Tc-receptor. Peripheral blood mononuclear cells (PBMC) were preactivated by anti-CD3 for 96 h following restimulation by anti-CD3, interleukin (IL)-2 and other mitogens. In control experiments unstimulated PBMC were incubated in medium alone. Immunophenotypes were analysed by flow cytometry. Cytokine production was determined by reverse transcription-polymerase chain reaction and intracellular signalling protein contents of Tc were compared by Western blotting. Furthermore, apoptosis was detected by terminal deoxyribose transferase-mediated deoxyuridine triphosphate nick end labelling assay. Unstimulated PBMC proliferate well after subsequent stimulation with anti-CD3, whereas IL-2 induces only limited proliferation. In contrast, preactivated cells respond only minimally to restimulation with anti-CD3, but IL-2 induces a marked proliferation. Both preactivated and unstimulated Tc respond well to restimulation by phytohaemagglutinin (PHA). In contrast, preactivated Tc show only a weak response to concanavalin A. Interestingly, when cells have been allowed to rest for 168 h, the responsiveness of preactivated Tc is restored. Immunoblots reveal that preactivated cells have a higher intracellular content of zeta-chain and p56lck. No differences are found concerning apoptosis after restimulation with anti-CD3 or the expression of ERK 1/2. The unresponsiveness to restimulation is due to an impairment of the transcription of the IL-2 gene and this defect is temporary. Despite the lack of proliferation, preactivated Tc phenotypically maintain an intermediate stage of activation. These data show how the same cell population can change its functional phenotype into a non-responder state.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Treating rheumatoid arthritis with new disease modifying drugs.

Rheumatoid arthritis (RA) is a serious illness that can only be controlled by the appropriate use of disease modifying anti-rheumatic drugs (DMARDs). In spite of the successful use of such substances, and of methotrexate in particular, a large number of patients still experience disease progression. Leflunomide and the two anti-TNF agents, infliximab and etanercept, were therefore warmly greeted as very welcome additions to the rheumatologist's armamentarium. These successful newcomers, their strengths and problems are the focus of the present review.

Adjuvants, Immunologic↗
PubMed2002

T lymphocyte activation--an inside overview.

Activated T lymphocytes play an important role in autoimmune disease. The process of T-cell activation is therefore of significant importance in understanding the pathogenesis of many rheumatic diseases. This process can be observed from outside the lymphocyte, but we have also gained increased understanding of many of the intracellular events of T-cell activation. This review tries to draw out the most important receptors, pathways, and transcription factors involved in the process.

Animals↗
PubMed2002

Increased bioactive TNF in human systemic lupus erythematosus: associations with cell death.

In systemic lupus erythematosus (SLE) serum TNF is increased and correlates with its soluble receptors and with disease activity. We therefore investigated (i) whether the TNF in SLE serum is bioactive, (ii) whether SLE cells react to TNF and (iii) whether there are associations with cell death, which is regarded as pathogenic in SLE. Sera from active SLE patients induced an increase in fibroblast CD54, which was abolished by blocking antibodies against TNF, suggesting TNF bioactivity. SLE lymphocytes had a similar surface expression of TNF-RI as healthy lymphocytes, their expression of TNF-RII was slightly increased. Recombinant TNF induced cell death in PBMC of SLE patients, suggesting functional receptors. Serum levels of sTNF-RII (as a surrogate marker for TNF activity) correlated with sTNF-RI and disease activity, as expected, and also correlated with the percentage of dying lymphocytes and with lymphocytic CD95. SLE sera contain increased amounts of biologically active TNF. Peripheral blood lymphocytes of SLE patients express functional TNF receptors. Finally, associations with cell death and CD95 receptors suggest that TNF may be pathogenic in SLE.

Adult↗
PubMed2001

Cancer polyarthritis resembling rheumatoid arthritis as a first sign of hidden neoplasms. Report of two cases and review of the literature.

Recent onset arthritis reminiscent of rheumatoid arthritis (RA) may be an early manifestation of an occult malignancy. In this report, we present two patients with cancer-associated polyarthritis. Both suffered from symmetric polyarthritis when initially visiting their physicians and did not achieve relief when treated with non-steroidal anti-rheumatic drugs (NSAIDs). In both patients, subsequent work-up led to the diagnosis of an underlying malignancy. One patient suffered from small cell lung cancer (SCLC), while the other was diagnosed with adenocarcinoma of the colon. In both, the arthritis spontaneously disappeared after successful treatment of the malignancy, i.e. chemotherapy and tumor resection, respectively. We discuss these cases in view of the existing literature, since awareness of the entity of cancer polyarthritis is necessary for its timely treatment and may potentially be life-saving.

Adenocarcinoma↗
PubMed2001

Serum interleukin-15 is elevated in systemic lupus erythematosus.

OBJECTIVE: To investigate if interleukin-15 (IL-15) (rather than IL-2) is increased in systemic lupus erythematosus (SLE) and might be responsible for immunological abnormalities of SLE such as the increased lymphocytic expression of Bcl-2 and CD25. METHODS: Serum IL-15, IL-2 and tumour necrosis factor (TNF) levels of 65 SLE patients, 20 healthy persons and 10 rheumatoid arthritis (RA) patients were measured by enzyme-linked immunosorbent assay (ELISA). For 25 SLE patients, the percentage of CD25 + lymphocytes and the lymphocytic Bcl-2 levels were simultaneously determined by fluorocytometry. Peripheral blood mononuclear cells (PBMC) of 15 SLE patients were incubated with or without recombinant IL-15 and the influence on Bcl-2 and CD25 was determined. RESULTS: IL-15 was found to be elevated in 25 SLE sera (38%), but in none of the 20 healthy sera (P = 0.0005) and none of the 10 RA sera. Both lymphocyte CD25 and Bcl-2 expression significantly correlated with serum IL-15 and were increased by recombinant IL-15. CONCLUSION: Serum IL-15 may in part be responsible for the immunological abnormalities seen in active SLE.

Adult↗
PubMed2000

The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.

Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation. We recently identified the gene causing FMF, designated MEFV, and found it to be expressed in mature neutrophils, suggesting that it functions as an inflammatory regulator. To facilitate our understanding of the normal function of MEFV, we extended our previous studies. MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization. CD34 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment. The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation. MEFV was also expressed in the monocytic cell lines U937 and THP-1. Among peripheral blood leukocytes, MEFV expression was detected in neutrophils, eosinophils, and to varying degrees, monocytes. Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements. In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN) gamma, tumor necrosis factor, and lipopolysaccharide induced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta inhibited such expression. Induction by IFN-gamma occurred rapidly and was resistant to cycloheximide. IFN-alpha also induced MEFV expression. In granulocytes, MEFV was up-regulated by IFN-gamma and the combination of IFN-alpha and colchicine. These results refine understanding of MEFV by placing the gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an IFN-gamma immediate early gene.

Cell Differentiation↗
PubMed2000

Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation.

Stat4 is a key transcription factor involved in promoting cell-mediated immunity, whose expression in mature cells has been reported to be restricted to T and NK cells. We demonstrate here, however, that Stat4 expression is not restricted to lymphoid cells. In their basal state, monocytes do not express Stat4. Upon activation, however, IFN-gamma- and LPS-treated monocytes and dendritic cells express high levels of Stat4. Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-alpha, but not IL-12. In contrast, the Th2 cytokines, IL-4 and IL-10, specifically down-regulate Stat4 expression in activated monocytes, while having little effect on Stat6 expression. Moreover, macrophages in synovial tissue obtained from patients with rheumatoid arthritis express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated human disease. IFN-alpha-induced Stat4 activation in human monocytes represents a previously unrecognized signaling pathway at sites of Th1 inflammation.

Arthritis, Rheumatoid↗
PubMed2000

Successful treatment of high turnover osteoporosis in a patient with adrenocortical insufficiency.

We present a case of high-turnover osteoporosis associated with substituted adrenocortical insufficiency (Addison's disease) and its successful treatment with calcitonin and calcitriol. A 43-year-old man presented with markedly reduced bone mineral density (BMD) (lumbar spine BMD -3.46 SD below healthy young adults) after thirteen years of glucocorticoid substitution. Interestingly, his osteocalcin levels indicated an unusually high bone turnover and his alkaline phosphatase levels were also increased. Combination treatment with calcitriol and calcitonin was started. Re-evaluation after twelve months revealed a substantial increase in BMD (+6.8% for the lumbar spine, +15% for the left hip). Alkaline phosphatase levels had normalised and osteocalcin was nearly down to normal. In spite of a thorough evaluation, no other cause of osteoporosis was detected. We discuss these findings in view of the existing literature.

Addison Disease↗
PubMed2000

Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes.

Glucocorticoids are widely used in the therapy of inflammatory, autoimmune, and allergic diseases. As the end-effectors of the hypothalamic-pituitary-adrenal axis, endogenous glucocorticoids also play an important role in suppressing innate and cellular immune responses. Previous studies have indicated that glucocorticoids inhibit Th1 and enhance Th2 cytokine secretion. IL-12 promotes Th1 cell-mediated immunity, while IL-4 stimulates Th2 humoral-mediated immunity. Here, we examined the regulatory effect of glucocorticoids on key elements of IL-12 and IL-4 signaling. We first investigated the effect of dexamethasone on IL-12-inducible genes and showed that dexamethasone inhibited IL-12-induced IFN-gamma secretion and IFN regulatory factor-1 expression in both NK and T cells. This occurred even though the level of expression of IL-12 receptors and IL-12-induced Janus kinase phosphorylation remained unaltered. However, dexamethasone markedly inhibited IL-12-induced phosphorylation of Stat4 without altering its expression. This was specific, as IL-4-induced Stat6 phosphorylation was not affected, and mediated by the glucocorticoid receptor, as it was antagonized by the glucocorticoid receptor antagonist RU486. Moreover, transfection experiments showed that dexamethasone reduced responsiveness to IL-12 through the inhibition of Stat4-dependent IFN regulatory factor-1 promoter activity. We conclude that blocking IL-12-induced Stat4 phosphorylation, without altering IL-4-induced Stat6 phosphorylation, appears to be a new suppressive action of glucocorticoids on the Th1 cellular immune response and may help explain the glucocorticoid-induced shift toward the Th2 humoral immune response.

3T3 Cells↗
PubMed2000

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus.

Both faulty regulation of apoptosis and the inappropriate expression of several interleukins have been considered important defects of lymphocytes in the human autoimmune disease systemic lupus erythematosus (SLE). We therefore tested the in vitro effect of recombinant interleukin (IL-)-2, 4, 7, and 15 on peripheral blood mononuclear cells from patients with SLE and from healthy volunteers. Intracellular Bcl-2 and Bax expression was measured by fluorocytometry and the rate of apoptosis was determined by the TUNEL technique and propidium iodide staining. IL-2, IL-4, IL-7 and IL-15 led to a significant increase in Bcl-2 and a reduction in cell death rates, which was even more pronounced in SLE. Bax levels remained unchanged. Interestingly, the high ex vivo Bcl-2 content of lymphocytes from some SLE patients was maintained after growth factor withdrawal. Anti-apoptotic cytokine signaling may significantly influence the deregulation of cell death in SLE lymphocytes.

Adolescent↗
PubMed2000

Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis.

OBJECTIVES: Both increased and decreased apoptosis may be involved in generating autoimmunity. This study addressed the question of whether apoptosis and apoptosis-regulating proteins are altered in systemic sclerosis (SSc). Patients and methods. Peripheral lymphocytes of 39 SSc patients and 47 healthy control persons were studied for apoptosis, Bcl-2 and Bax levels, expression of Fas (CD95) and activation markers (CD25, HLA-DR) as determined by fluorocytometry. Serum Fas and Fas ligand were measured by ELISA. RESULTS: SSc lymphocytes (mainly CD4(+)) expressed increased amounts of Bcl-2, while Bax was not elevated. Apoptosis rates of SSc lymphocytes were increased in unsupplemented medium, but returned to normal in the presence of autologous plasma. SSc patients had increased percentages of activated and CD95(+) lymphocytes and elevated soluble Fas and soluble FasL levels in serum. Activating anti-CD95 antibodies further increased the apoptosis rate. CONCLUSIONS: Increased in vitro apoptosis, elevated lymphocytic Bcl-2 content and the increased number of Fas-positive T cells are not specific for peripheral blood from SSc patients, but indicate deregulation of lymphocyte homeostasis in this disease.

Adult↗
PubMed1999

Ultrasound therapy for calcific tendinitis of the shoulder.

BACKGROUND AND METHODS: Although ultrasound therapy is used to treat calcific tendinitis of the shoulder, its efficacy has not been rigorously evaluated. We conducted a randomized, double-blind comparison of ultrasonography and sham insonation in patients with symptomatic calcific tendinitis verified by radiography. Patients were assigned to receive 24 15-minute sessions of either pulsed ultrasound (frequency, 0.89 MHz; intensity, 2.5 W per square centimeter; pulsed mode, 1:4) or an indistinguishable sham treatment to the area over the calcification. The first 15 treatments were given daily (five times per week), and the remainder were given three times a week for three weeks. Randomization was conducted according to shoulders rather than patients, so a patient with bilateral tendinitis might receive either or both therapies. RESULTS: We enrolled 63 consecutive patients (70 shoulders). Fifty-four patients (61 shoulders) completed the study. There were 32 shoulders in the ultrasound-treatment group and 29 in the sham-treatment group. After six weeks of treatment, calcium deposits had resolved in six shoulders (19 percent) in the ultrasound-treatment group and decreased by at least 50 percent in nine shoulders (28 percent), as compared with respective values of zero and three (10 percent) in the sham-treatment group (P=0.003). At the nine-month follow-up visit, calcium deposits had resolved in 13 shoulders (42 percent) in the ultrasound-treatment group and improved in 7 shoulders (23 percent), as compared with respective values of 2 (8 percent) and 3 (12 percent) in the sham-treatment group (P=0.002). At the end of treatment, patients who had received ultrasound treatment had greater decreases in pain and greater improvements in the quality of life than those who had received sham treatment; at nine months, the differences between the groups were no longer significant. CONCLUSIONS: In patients with symptomatic calcific tendinitis of the shoulder, ultrasound treatment helps resolve calcifications and is associated with short-term clinical improvement.

Calcinosis↗
PubMed1999

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Amino Acid Sequence↗
PubMed1999

Janus kinases and their role in growth and disease.

Janus kinases (JAK) play a crucial role in the initial steps of cytokine signaling. Each of the four members (JAK1, JAK2, JAK3, TYK2) of this non-receptor tyrosine kinase family is indispensable for the effects of distinct cytokines. Moreover, recent reports have added to our knowledge on their highly specific functions: JAK3 knockout mice and JAK3 deficient patients cannot signal through the interleukin-2,4,7,9, or 15 receptors and suffer from severe combined immunodeficiency (SCID). JAK1 and JAK2 knockout mice do not survive, their cells again showing distinct patterns of cytokine signaling deficits. At the other end of the spectrum, JAK fusion proteins have been shown to play a role in leukemias. In addition, a new class of JAK-specific inhibitors was described by several groups, the CIS/SOCS/Jab family. This review on the rapidly growing field focuses on JAK function and regulation, and on their emerging role in development and human disease.

Animals↗
PubMed1999

Expression of adhesion molecules on synovial fluid and peripheral blood monocytes in patients with inflammatory joint disease and osteoarthritis.

OBJECTIVE: To determine the presence of adhesion molecules on monocytes/macrophages (Mphi) from peripheral blood (PB) and synovial fluid (SF) in patients with osteoarthritis (OA) and inflammatory joint diseases (rheumatoid (RA) and reactive arthritis (ReA)) in order to improve our understanding of the possible mechanisms underlying the inflammatory process. METHODS: Whole blood and SF cells were stained with monoclonal antibodies against CD11a (LFA-1), CD15 s (sialyl-Lewis X), CD44, CD54, VLA-4, and HLA-DR counterstained with anti-CD14 antibodies as a Mphi marker for dual fluorescence analysis by flowcytometry. RESULTS: On PB-Mphi, CD15s was markedly increased in both RA as well as ReA compared with OA. Furthermore, in the PB LFA-1, CD44, and HLA-DR showed a higher surface density on Mphi in ReA than in OA. Comparison between SF and PB showed significantly higher CD44 and CD54 expression on SF-Mphi. These molecules play an important part in lymphocyte-Mphi interaction. CONCLUSION: In PB from patients with inflammatory joint diseases, Mphi are activated, allowing recruitment into the synovial compartment. These disorders, in contrast with OA seem to be "systemic" in nature. Within the SF, different adhesion molecules are expressed on CD14(+) Mphi as compared with PB.

Adult↗