Higher Levels Of sFas Research Articles

Altered Immune Response in Severe Malaria Anemia in Children.

We prospectively assessed immune markers in children <6 years with severe malarial anemia (hemoglobin <5.0 g/dL; n = 72) and uncomplicated malaria (n = 69) who presented to Macha Mission Hospital in Zambia's Southern Province. We also studied 70 children <6 years who presented to well child clinics in Harare, Zimbabwe as controls. Compared to controls, children with uncomplicated malaria had significantly higher temperatures and parasite counts, lower hemoglobin and platelet concentrations, higher plasma levels of interferon-gamma, tumor necrosis factor alpha, and interleukin 10 and lower levels of monocyte inhibitory factor (MIF). Compared to uncomplicated malaria, severe malaria anemia was associated with younger age, longer duration of fever and lower temperature on admission. Reticulocyte index and serum concentrations of bilirubin and LDH did not differ between the malaria groups, suggesting that unusually severe extra- or intra-medullary hemolysis did not explain the severe anemia. Higher white blood cell and platelet counts in the severe malaria group suggested that pan-suppression of the marrow was also not the primary cause. Of originally selected measures of inflammation, plasma levels of TNF-alpha and MIF did not differ between the malaria groups, but concentrations of both interferon-gamma and interleukin-10 were significantly lower in the severe anemia group (P <0.006). Additional testing revealed levels of interleukin-1alpha, interleukin-6, and IP-10 to be lower and levels of sFAS to be higher in the children with severe anemia versus uncomplicated malaria (P <0.0005). In a logistic regression model, severe malarial anemia was associated with younger age (P = 0.010), prior treatment with sulfadoxine/pyrimethamine or traditional medicine (P <0.32), lower levels of Interleukin-10 (P = 0.025) and higher levels of sFAS (P = 0.003) and TNFa (P = 0.013). Our results are consistent with a multifactorial cause of severe malarial anemia, possibly including infection with resistant plasmodia, over-expression of TNF-alpha in conjunction with under-expression of IL-10, and increased apoptosis.

Soluble Fas—A promising novel urinary marker for the detection of recurrent superficial bladder cancer

The objective of this study was to test the hypothesis that elevated urinary levels of soluble Fas (sFas) would aid in the surveillance of patients with a past history of nonmuscle-invasive transitional cell carcinoma (TCC) of the urinary bladder. sFas levels were determined in cell lysates and supernatants from 2 human bladder cancer cell lines (T24 and TCC-SUP) and in voided urine from 188 consecutive patients who were at risk for TCC recurrence, 31 patients who had noncancerous urologic conditions, and 10 healthy individuals. The authors also obtained barbotage cytology and voided nuclear matrix protein 22 (NMP22) levels. sFas was analyzed continuously and categorically on the basis of its quintile distribution. sFas was present in cell lysates and conditioned media from both cell lines. sFas levels were found to be higher in the TCC group (n = 122 patients) compared with the control group (P < .001). Higher levels of sFas were associated with positive cytology assay results (P < .001), higher NMP22 levels (P < .001), NMP22 levels > 10 U/mL (P < .001), and tumor stage > or = T1 (P < .001). The areas under the receiver operating characteristics (ROC) curves of sFas and NMP22 for bladder cancer detection were 0.757 (95% confidence interval, 0.694-0.819) and 0.704 (95% confidence interval, 0.637-0.772), respectively. In the > 75% sensitivity region of the ROC curves, sFas was consistently more specific than NMP22. In multivariate analyses, sFas, NMP22, and cytology all were found to be associated with the presence of bladder cancer (P values < or = .009), but only sFas and cytology were associated with tumor stage > or = T1 (P values < or = .026). sFas was produced and released by bladder TCC cells. Urine sFas was an independent predictor of bladder cancer recurrence and invasiveness in patients who had a past history of nonmuscle invasive bladder TCC, and it outperformed NMP22.

Modulation of sFas indicates apoptosis in human herpes simplex encephalitis

Herpes simplex encephalitis (HSE) is the most common cause of non-epidemic, acute and fatal viral encephalitis. A pronounced mortality and morbidity remains in HSE despite antiviral treatment. There is evidence of a vigorous intrathecal immune activity in acute phases of HSE and of persistently increased activity at follow-ups after years. The role of apoptosis of neuronal cells in HSE patients as a mechanism of damage has been brought up lately. We hypothesize that the severity and the progression of the cerebral injury resulting from HSE can be evaluated by quantitative measurement of a compartment of immune activation molecules i.e. soluble Fas (sFas) involved in apoptosis through the Fas/Fas Ligand pathway. Consecutive cerebrospinal fluid (CSF) samples from a prospectively followed cohort, included in an antiviral treatment trial in HSE, were enrolled for quantitative measurement of sFas using commercial capture ELISA. In total, CSF samples from 49 patients with HSE, 63 patients with non-HSE encephalitis and 18 healthy individuals were studied. High levels of sFas were expressed in CSF samples collected between days 0–45 after neurological onset in 41 / 49 (84%) HSE patients, whereas only 21 / 63 (33%) of non-HSE patients and none of 18 healthy controls demonstrated measurable levels of sFas. Following the consecutive CSF sFas levels over the time and considering the clinical state of patients at admission, their neurological or lethal outcome at 12 months, and antiviral treatment, we observed that HSE patients with severe neurological sequels revealed an increase in changes of CSF sFas as compared to patients with mild or moderate neurological outcome (57.6 ± 55.6 pg/ml, n = 10 versus 26.3 ± 97.5 pg/ml, n = 14; P = 0.008). Also HSE patients undergoing vidarabine treatment expressed significantly higher levels of changes of CSF sFas when compared to acyclovir-treated patients (63.7 ± 52.8 pg/ml, n = 9 versus 26.1 ± 98.4 pg/ml, n = 14; P = 0.003). Interestingly, regardless of the clinical state at admission, and subsequent disease progression of the HSE patients, we could not observe any significant differences in the CSF sFas levels during the first 7 days of neurological symptoms. These observations underline the role of immunological response throughout the course of HSV infection in the brain and the role of the Fas/FasL pathway in particular in disease progression of HSE. The findings further enforce the need of expanding the knowledge of the pathogenesis of HSE to direct to more effective, in particular not only antiviral but also anti-apoptotic or anti-inflammatory treatment.

Soluble Fas receptor and soluble Fas ligand in the serum of women with uterine tumors

It is commonly accepted that apoptosis plays an important role in the death of normal and neoplastic cells. Related proteins and their receptors on cell surfaces regulate apoptosis. One of the best-characterized systems is the Fas-Fas ligand system. The aim of the study was to examine the concentrations of soluble Fas receptor (sFas) and the soluble ligand for the Fas receptor (sFasL) in serum of women with uterine tumors. The study included 42 women with uterine tumors. As a normal control, sera were obtained from 20 healthy female volunteers. The concentrations of sFas and sFasL in serum were measured by enzyme-linked immunosorbent assay ELISA. Significant increases of the mean value of sFas and sFasL were found in the serum of women with uterine tumor compared to the control group (p < 0.0001). The mean levels of these parameters increased in consecutive stages of the clinical extent of the uterine cancer (I-III). The lowest concentration was observed in women with stage I and the highest in women with stage III of clinical extent according to FIGO. Apoptosis that appears to occur in the cancerous cells of malignant uterine tumors is associated with high levels of sFas and sFasL in serum.

Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis

BackgroundAn altered susceptibility of lung fibroblasts to Fas-induced apoptosis has been implicated in the pathogenesis of pulmonary fibrosis; however, the underlying mechanism is not completely understood. Here, we studied the susceptibility of lung fibroblasts, obtained from patients with (f-fibs) and without pulmonary fibrosis (n-fibs), to FasL- (CD95L/APO-1) induced apoptosis in relation to the expression and the amounts of membrane-bound and soluble Fas. We also analysed the effects of tumor necrosis factor-β on FasL-induced cell death.MethodsApoptosis was induced with recombinant human FasL, with and without prior stimulation of the fibroblasts with tumor necrosis factor-α and measured by a histone fragmentation assay and flow cytometry. The expression of Fas mRNA was determined by quantitative PCR. The expression of cell surface Fas was determined by flow cytometry, and that of soluble Fas (sFas) was determined by enzyme-linked immunosorbent assay.ResultsWhen compared to n-fibs, f-fibs were resistant to FasL-induced apoptosis, despite significantly higher levels of Fas mRNA. F-fibs showed lower expression of surface-bound Fas but higher levels of sFas. While TNF-α increased the susceptibility to FasL-induced apoptosis in n-fibs, it had no pro-apoptotic effect in f-fibs.ConclusionsThe data suggest that lower expression of surface Fas, but higher levels of apoptosis-inhibiting sFas, contribute to the resistance of fibroblasts in lung fibrosis against apoptosis, to increased cellularity and also to increased formation and deposition of extracellular matrix.

Fas polymorphisms are associated with the presence of anti-ganglioside antibodies in Guillain–Barré syndrome

Polymorphisms in genes involved in regulation of immune homeostasis may be a susceptibility factor in the induction of cross-reactive anti-ganglioside antibodies after infection in patients with Guillain–Barré syndrome (GBS). In this study we assessed whether polymorphisms in the promoter region of Fas and FasL and sFas and sFasL are related to GBS or its distinct clinical or serological subgroups. We show that the A(−670)G SNP in the promoter region of Fas and high levels of sFas are associated with the presence of anti-ganglioside antibodies, suggesting that Fas–FasL interaction is involved in the production of cross-reactive antibodies in GBS.

Circulating soluble Fas levels in patients with hepatitis C virus infection and interferon therapy

The clinical relevance of the circulating soluble form of the Fas-Receptor (sFas) was investigated in patients with hepatitis C receiving type 1 interferon (IFN) therapy. sFas was quantified by enzyme-linked immunosorbent assay in 66 hepatitis C virus (HCV) carriers and 30 HCV-naive or previously infected controls. The levels were then monitored during enhanced treatment with type 1 IFNs in 15 chronic hepatitis C patients. The HCV carriers had high levels of sFas compared with controls (3.8+/-1.3 vs 2.7+/-0.8 ng/ml; P<0.001). sFas levels in patients with chronic HCV infection were directly related to serum alanine aminotransferase levels (r=0.440; P<0.001) and the histological grade (r=0.403; P=0.019). Among necroinflammatory reactions, only piecemeal necrosis showed a correlation with sFas levels (r=0.556; P=0.001). Pretreatment sFas levels, however, were not predictive of therapeutic outcomes. A sustained virological response to enhanced IFN therapy showed a relation to only the pretreatment HCV load. Interestingly, circulating sFas was upregulated when IFN-beta was administered at short intervals (3 MU/every 12 h). This upregulation was accompanied by parallel aminotransferase elevation, which was observed regardless of a virological response. sFas elevation, in parallel with the severity of liver injury, suggests the possible upregulation of hepatic Fas expression and the Fas-mediated pathway in both HCV- and type 1 IFN-induced liver injury. The essential function of sFas to protect hepatocytes against Fas-mediated liver injury was not evident in these clinical settings.

Prognostic Significance of Serum Soluble Fas Level and Its Change during Regression and Progression of Advanced Prostate Cancer

To evaluate the clinical usefulness of serum soluble Fas (sFas) and sFas ligand as a prognostic factor and for monitoring the regression and progression of metastatic prostate cancer treated with endocrine therapy, sFas and sFas ligand were measured in sera collected from 30 patients with untreated metastatic prostate cancer. sFas levels were measured sequentially in 16 patients who had progressed to a state of elevated prostate-specific antigen (PSA) and 5 patients who were in regression following endocrine therapy. Serum sFas levels in patients with metastatic prostate cancer were found to be significantly higher than that of control patients with benign prostate hyperplasia. Patients with low levels of serum sFas had a higher cause-specific survival rate and a higher PSA progression-free rate compared with patients with high levels of serum sFas. In patients who suffered PSA progression following endocrine therapy, serum sFas increased in parallel to the increase in PSA levels although the magnitude of change in sFas was very small. In patients whose tumor regressed following therapy, sFas levels did not change. sFas ligand levels were very low or below measurable levels in all specimens. sFas levels might be associated with poor prognosis in metastatic prostate cancer. Serum sFas ligand appears to have limited clinical relevance.

Serum levels of soluble Fas soluble Fas ligand and soluble IL-2 receptor in patients with coronary heart disease

OBJECTIVE: To evaluate the relationship between serum levels of soluble Fas(sFas), soluble Fas li gand(sFasL), soluble IL-2 receptor(sIL-2R) and coronary heart disease (CHD). METHODS: With enzyme-linked immunosorbent assay (ELISA) tests, sFas, sFasL and sIL-2R were measured in the sera from 30 patients with CHD and 26 subjects without CHD as controls. RESTULTS: Mean level of sFas was significantly higher in patients with CHD than in controls [(1 583.41+/-174.46)ng/L compared with (1 374.55+/-142.42)ng/L, P<0.01]. Compared with the controls, the mean level of sIL-2R was significantly higher in patients with CHD [(944.50+/-395.59)ng/L compared with (652.45+/-163.36)ng/L P<0.01]. Moreover, in patients with CHD sFas and sIL-2R were positively correlated (r=0.418 P<0.05). Whereas no such difference was found between both groups in sFasL (P<0.05). CONCLUSION: High levels of serum sFas and sIL-2R were associated with CHD, and elevation of sFas may inhibit apoptosis in activated T cells, leading to coronary events.

Relationship between plasma levels of cardiac natriuretic peptides and soluble Fas: Plasma soluble Fas as a prognostic predictor in patients with congestive heart failure

Background: Cardiac natriuretic peptides may induce apoptosis in myocytes; however, the relationship between plasma levels of cardiac natriuretic peptides and those of soluble Fas (sFas) and tumor necrosis factor (TNF)-α remains unknown in patients with congestive heart failure (CHF). Methods and Results: We measured plasma levels of sFas and TNF-α and those of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, and endothelin 1 in 96 patients with CHF (ejection fraction < 45%). The patients were monitored for 3 years. Plasma levels of sFas and TNF-α increased with the severity of CHF. There was no significant correlation between sFas plasma levels and those of ANP and BNP. Cox proportional hazard analysis showed that high levels of sFas (P =.009) and BNP (P <.0001) and a low ejection fraction (P =.019) were independent significant prognostic predictors. Conclusions: There is no significant correlation between cardiac natriuretic peptide and sFas levels in plasma. Plasma sFas is a useful prognostic marker independent of neurohumoral factors, suggesting that immune activation and/or apoptosis play a significant role in the pathogenesis of CHF.

Increased serum levels of soluble Fas in progressive B-CLL.

Clinical progression of B-cell chronic lymphocytic leukemia (B-CLL) depends on survival and accumulation of leukemic cells, regulated in part by physical cell contact and soluble molecules. Here we have studied the Fas/FasL system in relation to clinical progression in B-CLL. Serum levels of soluble Fas (sFas) and FasL (sFasL) were determined by ELISA in 43 progressive and 40 non-progressive B-CLL patients and in 21 control individuals. Correlation between sFas serum levels and clinical progression, stage and survival were statistically analyzed. We found high levels of sFas in B-CLL sera correlated with disease progression (p<0.01). In addition, higher sFas levels were found in patients in stages II, III and IV in comparison to patients in stage 0 (p<0.05, p<0.01, p<0.03, respectively). Survival was significantly shorter for patients with > or =6 ng/ml sFas serum levels, although a multivariate analysis did not show sFas to be a significant independent prognostic factor. Fresh B-CLL cells showed only low levels of membrane expression, which were not correlated to sFas levels in serum. In vitro activation of B-CLL cells increased Fas expression, as reported earlier, and induced cells to release sFas into the supernatant. In conclusion, our results indicate that sFas in serum may be a useful parameter for the prediction of clinical progression in B-CLL.

Discrepant expression of membrane and soluble isoforms of Fas (CD95/APO-1) in adult T-cell leukaemia: soluble Fas isoform is an independent risk factor for prognosis.

The Fas signalling system probably plays a critical role in the natural and chemotherapeutic cell death machinery, suggesting that aberrant Fas expression is involved in growth control of tumours. The membrane isoform (mFas) is a 45 kD cell surface protein containing a single transmembrane region, and induces apoptosis in normal or tumour cells, whereas the soluble isoform (sFas) lacks the transmembrane domain due to alternative splicing of the transcript and is thought to block Fas-mediated apoptosis. To clarify the clinical roles of expression of these two Fas isoforms in adult T-cell leukaemia (ATL), we investigated the levels of the Fas isoforms in 81 patients with ATL. The expression patterns of the Fas isoforms were heterogenous, and there was no significant correlation between mFas and sFas levels: 10/81 cases were negative for mFas and had high serum sFas levels, whereas the remaining 71 cases were positive for mFas and had various levels of expression of the two Fas isoforms. Irrespective of the status of mFas expression in leukaemic cells, the mRNAs encoding these isoforms were always detectable, indicating the potential for protein translation. Although mFas expressed on freshly isolated ATL cells could iduce apoptosis in vitro, positive versus negative mFas status was not associated with any clinical aspects of ATL, whereas the sFas level was strongly correlated with clinical parameters such as serum LDH activity, tumour burden, serum soluble IL-2R level, hypercalcaemia and prognosis. These results suggest that the ratio of Fas isoforms varies, and high expression of the sFas protein and message reflects the malignant behaviour of ATL and is an independent risk factor for the prognosis.

A high serum soluble Fas/APO-1 level is associated with a poor outcome of aggressive non-Hodgkin's lymphoma.

Soluble Fas (sFas) in the serum is believed to be able to inhibit apoptosis of lymphocytes. It has been reported that the serum sFas level is increased in various diseases, including malignant lymphoma and systemic lupus erythematosus. We studied the association between sFas and the prognosis of patients with aggressive non-Hodgkin's lymphoma (NHL). Compared with normal controls, the serum sFas level was increased significantly in patients with aggressive NHL and adult T cell leukemia/lymphoma. Among patients with aggressive NHL, the complete remission rate was significantly decreased in the subgroup having high serum sFas levels. Both the overall survival rate and the disease-free survival (DFS) rate were significantly lower for this subgroup than for patients with low serum sFas levels. The 5-year survival rates estimated by the Kaplan-Meier method for patients with high and low serum sFas levels were 27.6% and 68.3%, respectively (P = 0.0001). The 5-year DFS rates estimated for patients with high and low serum sFas levels were 44.7% and 71.9%, respectively (log-rank test: P = 0.0023, and generalized Wilcoxon test: P = 0.0014). Among patients with a low and low-intermediate risk group according to the International Prognostic Index (IPI), the 5-year survival rates for low and high serum sFas subgroups were 72.8% and 42.0%, respectively, showing a significant difference (Wilcoxon test: P = 0.0163, log-rank test: P = 0.0115). Among patients with a high-intermediate and high risk group, the 5-year survival rates for low and high serum sFas subgroups were 51.6% and 17.4%, respectively, again showing a significant difference (Wilcoxon test: P = 0.0001, log-rank test: P = 0.0002). Multivariate analysis of a series of prognostic factors, including the five used to calculate the IPI, showed that the serum sFas level was an independent prognostic factor for the overall survival. Based on these results, a serum sFas level of 10 ng/ml or more can be considered to indicate a poor prognosis in patients with advanced NHL, and this finding may be useful for developing strategies for further treatment.

Serum Levels of Soluble Fas and Disease Activity in Patients with IgA Nephropathy

Using a sandwich ELISA, we studied 48 patients with IgA nephropathy and 10 patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (non-IgA PGN) to determine if levels of serum soluble Fas (s-Fas) might reflect the disease activity. The levels of serum s-Fas in patients with the advanced stage of IgA nephropathy were significantly higher than those in patients with the mild stage of the disease, in non-IgA PGN or in healthy controls. The results showed that advanced stage IgA nephropathy patients who showed heavy proteinuria and the presence of urinary casts revealed high levels of serum s-Fas. It was thus suggested that the measurement of serum s-Fas is useful in evaluating the degree of renal injury in patients with IgA nephropathy.

PROGNOSTIC SIGNIFICANCE OF SOLUBLE FAS IN THE SERUM OF PATIENTS WITH BLADDER CANCER

Purpose The interaction of Fas antigen (Fas) and Fas ligand plays an important role in cytotoxic T lymphocyte- and natural killer cell-mediated cytotoxicity against cancer cells. Circulating soluble Fas (sFas) antagonizes cell-surface Fas function and may interfere with immune surveillance against autologous tumors. This possibility was examined in patients with bladder cancer. Materials and Methods The levels of sFas in the serum of 173 patients with bladder cancer were determined by using an enzyme-linked immunosorbent assay. Cytotoxicity of anti-Fas monoclonal antibody was examined by a 1-day microculture tetrazolium dye assay. Anti-autologous tumor cytotoxic activity was determined by the 12-hour 51 Cr release assay. Results The mean serum level of sFas in patients with bladder cancer was threefold higher than the mean in normal donors. The patients were divided into 2 groups based on the level of sFas in the serum. Bladder cancer patients with low level of serum sFas (less than the mean value) had a higher disease-specific survival rate, when compared with those with high level of serum sFas (greater than the mean value) in the 5-year followup. There were no statistical differences in patient's age and sex, as well as histological stage and grade of bladder cancer between the patients with high and low levels of serum sFas. Furthermore, patients with Ta bladder cancer with a low level of serum sFas had a longer postoperative tumor-free interval than those with high level in the 5-year followup. Cytotoxic activity of peripheral blood lymphocytes against autologous tumor cells was examined in 25 patients. There was an inverse correlation between the level of serum sFas and anti-autologous tumor cytotoxicity. Conclusions The findings suggest that elevated levels of sFas in the serum might be associated with poor prognosis in patients with bladder cancer.

Soluble Fas Levels in Sera of Bone Marrow Transplantation Recipients Are Increased During Acute Graft-Versus-Host Disease But Not During Infections

AbstractGraft-versus-host disease (GVHD) and infections are two major complications of allogeneic bone marrow transplantation (BMT). In the course of GVHD, one of the pathways that activated cytotoxic T cells use to execute their killing mechanisms is the Fas/Fas ligand pathway. This killing mechanism might be accompanied by the release of soluble Fas (sFas) in the circulation. To examine the association of serum sFas levels and post-BMT complications, we have analyzed sFas levels in sera of bone marrow recipients with and without GVHD. Postallogeneic BMT sFas levels were significantly increased during clinically relevant acute GVHD (aGVHD; P = .002). However, during infections sFas levels tended to decrease (P = .088). Yet, the simultaneous occurrence of GVHD and infections resulted in extreme high sFas levels. These results suggested that sFas release may be correlated with the amount of tissue damage, because aGVHD induces more damage than infections. The presence of significantly increased sFas levels during aGVHD provides new insights into the GVHD pathogenesis.

Soluble Fas (APO-1, CD95) and soluble Fas ligand in rheumatic diseases.

To assess levels of soluble Fas (sFas) and soluble Fas ligand (sFas-L) in sera from patients with various rheumatic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), mixed connective tissue disease (MCTD), and Sjogren's syndrome (SS). Levels of sFas and sFas-L were determined by a sandwich enzyme-linked immunosorbent assay. In SLE, PM/DM, MCTD, and SS, sFas levels were significantly higher compared with normal controls. Levels of sFas in the SLE patients were significantly higher than in patients with other rheumatic diseases. Levels of sFas-L were significantly increased in SS patients. SLE and RA patients with high levels sFas-L tended to have high levels of sFas, while sFas and sFasL levels did not correlate in patients with other diseases. In some of the SLE patients, sFas and sFas-L levels decreased following steroid therapy. Serum sFas and sFas-L levels were significantly higher in some rheumatic disease patients. Since these changes are complex in these rheumatic diseases, it may be difficult to directly relate sFas and sFasL to their pathogenesis.