Alterations in immune and renal biomarkers among workers occupationally exposed to low levels of trichloroethylene below current regulatory standards.

OBJECTIVES: The occupational exposure limit for trichloroethylene (TCE) in different countries varies from 1 to 100 ppm as an 8-hour time-weighted average (TWA). Many countries currently use 10 ppm as the regulatory standard for occupational exposures, but the biological effects in humans at this level of exposure remain unclear. The objective of our study was to evaluate alterations in immune and renal biomarkers among workers occupationally exposed to low levels of TCE below current regulatory standards. METHODS: We conducted a cross-sectional molecular epidemiology study of 80 healthy workers exposed to a wide range of TCE (ie, 0.4-229 ppm) and 96 comparable unexposed controls in China, and previously reported that TCE exposure was associated with multiple candidate biological markers related to immune function and kidney toxicity. Here, we conducted further analyses of all of the 31 biomarkers that we have measured to determine the magnitude and statistical significance of changes in the subgroup of workers (n=35) exposed to <10 ppm TCE compared with controls. RESULTS: Six immune biomarkers (ie, CD4+ effector memory T cells, sCD27, sCD30, interleukin-10, IgG and IgM) were significantly decreased (% difference ranged from -16.0% to -72.1%) and one kidney toxicity marker (kidney injury molecule-1, KIM-1) was significantly increased (% difference: +52.5%) among workers exposed to <10 ppm compared with the control group. These associations remained noteworthy after taking into account multiple comparisons using the false discovery rate (ie, <0.20). CONCLUSION: Our results suggest that occupational exposure to TCE below 10 ppm as an 8-hour TWA may alter levels of key markers of immune function and kidney toxicity.

Association between Helicobacter pylori infection and tumor markers: an observational retrospective study.

OBJECTIVE: Helicobacter pylori infection is a major cause of several cancers such as gastric, pancreatic and lung. The relationship between H. pylori and tumour markers continues to remain unclear. The primary goal of this study is to clarify the associations between H. pylori infection and six tumour markers (ie, carcinoembryonic antigen (CEA), cancer antigen (CA) 153, CA199, CA724, CA125 and alpha-fetoprotein (AFP)). The secondary goal is to provide understanding for further research about H. pylori infection and gastrointestinal cancer. DESIGN: Observational retrospective study. SETTING: The study was performed in Beijing, China, where enrolled subjects had all passed health examinations during the period of 2012-2016. Subjects were categorised into H. pylori (+) and H. pylori (-) group according to their infection status and the measured six biomarkers. We used logistic regression models and generalised linear models to explore the associations between H. pylori infection and six tumour markers (ie, CEA, CA153, CA199, CA724, CA125 and AFP). PARTICIPANTS: A total of 14 689 subjects were included and 6493 (44.2%) subjects were infected by H. pylori. The subjects had a mean age (1SD) of 45 (18) years. There were 4530 (31.0%) female subjects. RESULTS: After adjusting for the confounding factors, infections with H. pylori were found to be significantly associated with abnormal ratios in CEA, AFP and CA724 of H. pylori (+) to H. pylori (-) groups. Significant positive correlation was found between H. pylori infection and CEA values (adjusted ß=0.056; 95% CI 0.005 to 0.107; p=0.033). CONCLUSIONS: In this observational retrospective study, we observed the H. pylori infections in a Chinese population and found higher CEA level in H. pylori-infected subjects and abnormal ratios in CEA, AFP and CA724 in infected subjects to uninfected subjects. These findings may provide a basis for future exploration with H. pylori and tumour markers.

Association of CD30 transcripts with Th1 responses and proinflammatory cytokines in patients with end-stage renal disease.

High serum sCD30 levels are associated with inflammatory disorders and poor outcome in renal transplantation. The contribution to these phenomena of transcripts and proteins related to CD30-activation and -cleavage is unknown. We assessed in peripheral blood of end-stage renal disease patients (ESRDP) transcripts of CD30-activation proteins CD30 and CD30L, CD30-cleavage proteins ADAM10 and ADAM17, and Th1- and Th2-type immunity-related factors t-bet and GATA3. Additionally, we evaluated the same transcripts and release of sCD30 and 32 cytokines after allogeneic and polyclonal T-cell activation. In peripheral blood, ESRDP showed increased levels of t-bet and GATA3 transcripts compared to healthy controls (HC) (both P<0.01) whereas levels of CD30, CD30L, ADAM10 and ADAM17 transcripts were similar. Polyclonal and allogeneic stimulation induced higher levels of CD30 transcripts in ESRDP than in HC (both P<0.001). Principal component analysis (PCA) in allogeneic cultures of ESRDP identified two correlation clusters, one consisting of sCD30, the Th-1 cytokine IFN-γ, MIP-1α, RANTES, sIL-2Rα, MIP-1ß, TNF-ß, MDC, GM-CSF and IL-5, and another one consisting of CD30 and t-bet transcripts, IL-13 and proinflammatory proteins IP-10, IL-8, IL-1Rα and MCP-1. Reflecting an activated immune state, ESRDP exhibited after allostimulation upregulation of CD30 transcripts in T cells, which was associated with Th1 and proinflammatory responses.

Elevated Serum Levels of Soluble CD30 in Ankylosing Spondylitis Patients and Its Association with Disease Severity-Related Parameters.

Soluble CD30 (sCD30), a transmembrane glycoprotein that belongs to the tumor necrosis factor receptor (TNFR) superfamily, has been shown to be associated with various pathological conditions. This study was designed to measure the levels of serum sCD30 in patients with ankylosing spondylitis (AS) and to evaluate the relationships between serum sCD30 levels and other disease severity-related indexes, including bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS), and bath ankylosing spondylitis functional index (BASFI). Our results demonstrated significantly elevated sCD30 levels in AS patients compared to healthy controls (HCs) with mean values of 32.0 ± 12.2 and 24.9 ± 8.0 ng/mL, respectively (P(**) = 0.007), suggesting a potential role of sCD30 in the pathogenesis of AS. However, no significant correlations of sCD30 with BASDAI, ASDAS, or BASFI were detected in our study (P > 0.05). Therefore, sCD30 cannot be used as a reliable marker for reflecting disease activity and functional ability of AS patients.

[Soluble apoptosis markers in obese patients with food intolerance].

For the soluble apoptosis markers study 151 patients with obesity (92 women and 59 men) aged between 18 and 63 years were examined. Diagnosis and degree of obesity was based on the body mass index (38.2 +/- 5.4 kg/m2). Generally food intolerance was identified in 36.4% of obese patients. Four groups of patients were formed: three groups of patients with obesity stage I (15 patients), II (18 patients) and III (22 patients), respectively, and with food intolerance, and a group of obese patients without food intolerance (control group, n = 31). Obese patients with food intolerance received standard version of hypocaloric diet with the exception of specific food allergens. Duration of observation was 39-43 days. Such soluble apoptosis markers as sFas-L, Caspase-9, Caspase-8 and sCD153 were significantly higher in stage III obesity patients compared obese patients without food allergy (0.120 +/- 0.030 vs 0.035 +/- 0.010; 13.2 +/- 3.2 vs 5.9 +/- 0.4; 1.4 +/- 0.18 vs 0.6 +/- 0.24; 0.123 +/- 0.010 vs 0.025 +/- 0.002 ng/ml respectively). Positive dynamic of sFas-L, Caspase-9 and Caspase-8 (decrease to 0.052 +/- 0.030; 7.7 +/- 2.2 and 0.4 +/- 0.18 ng/ml respectively) in patients with obesity stage III and intactness sCD153 during diet therapy course were revealed. Significant differences for only Caspase-9 in patients with obesity stage II were obtained. The data obtained are considered as normalization of apoptosis due to nutritional correction of immunological disorders. Study of sFas-L, Caspase-9 and Caspase-8 allows to predict the course of disease, as immunological research for early detection of food allergy makes possible to implement the principles of personalized diet therapy.

CD30 in systemic mastocytosis.

CD30 is a transmembrane receptor, normally not expressed by mast cells, which regulates proliferation/apoptosis and antibody responses. Aberrant expression of CD30 by mastocytosis mast cells and interaction with its ligand CD30L (CD153) appears to play an important role in the pathogenesis and clinical presentation of systemic mastocytosis. This article highlights the expression profile and role of CD30 and CD30L in physiologic and pathologic conditions, the applicability of CD30 as a marker for systemic mastocytosis, the consequences of mast cell-expressed CD30, and the possibility of future anti-CD30 based cytoreductive therapies.

Cytokines as potential biomarkers of liver toxicity induced by Dioscorea bulbifera L.

The present study is designed to search for the serum cytokine biomarker for liver injury induced by Dioscorea bulbifera L., which is a traditionally used herbal medicine in China. Mice were orally given various doses of ethyl acetate extract (EF) isolated from D. bulbifera for 12 days. The activity of serum alanine/aspartate transaminases (ALT/AST) was increased in EF (400 mg/kg)-treated mice. Histological assessment further confirmed EF (400 mg/kg)-induced liver injury. Results of a cytokine-antibody array demonstrated that there were 10 cytokines up-regulated and 1 cytokine down-regulated in EF (400 mg/kg)-treated mice. Enzyme-linked immunosorbent assay (ELISA) further confirmed the increased level of CD30 ligand (CD30L) and decreased level of interlukin-3 (IL-3) in EF-treated mice. In conclusion, our results demonstrate that the altered expression of CD30L and IL-3 may be potential biomarkers for hepatotoxicity induced by D. bulbifera.

In rheumatoid arthritis soluble CD30 ligand is present at high levels and induces apoptosis of CD30(+)T cells.

CD30 and CD30 ligand (CD30L) are members of TNF-receptor and TNF superfamilies respectively. CD30(+)T cells are increased in several diseases and interaction between CD30(+) and CD30L(+)T cells leads either to cell proliferation or apoptosis. In patients with rheumatoid arthritis (RA), soluble CD30 (sCD30) levels seem to reflect the recruitment of CD30(+)T cells into the inflamed joints and are predictive of a positive response to classical and biological immunosuppressive therapy. We have evaluated the presence of soluble CD30L (sCD30L) in the sera and synovial fluid of patients with RA and defined whether it binds surface CD30 molecule and is functionally active. We found high levels of sCD30L in sera and synovial fluid of RA patients; the molecule is shedded upon direct contact of CD30(+)/CD30L(+)T cells. Moreover sCD30L binds surface CD30 constitutively expressed by Jurkat cell line. Finally recombinant sCD30L and sera from patients with high levels of sCD30L are able to inhibit CD30(+)T cell proliferation by inducing cell apoptosis. Our findings suggest that circulant sCD30L is functionally active and that it may favor persistence of active inflammation by inducing apoptosis of CD30(+)T cells, known to down-modulate inflammation in rheumatoid synovitis.

A differential impact of mycophenolic acid, prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients.

BACKGROUND: Soluble CD30 (sCD30) has been associated with rejection and graft loss in kidney transplantation, leading to the suggestion that sCD30 might be a useful biomarker to adjust immunosuppressant medication dosing. However, there has been minimal study of the influence of individual immunosuppressive drugs on sCD30 levels. AIM: To evaluate the influence of mycophenolic acid (MPA), prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients. METHODS: The sCD30 levels were measured pretransplant and 30 days posttransplant. Area under the concentration-time curve (AUC) for each drug was estimated on day 30 using validated, multiple regression-derived limited sampling strategies. RESULTS: One hundred twenty-five subjects were included. Median (interquartile range) sCD30 levels were lower on day 30 posttransplant compared with pretransplant [10.7 (3.7-20.1) pg/mL versus 66.5 (46.0-95.1) pg/mL; P < 0.0001]. On univariate analyses, day 30 sCD30 levels were negatively correlated with MPA exposure and positively correlated with tacrolimus exposure. Using multivariate logistic regression, higher tacrolimus exposure was independently associated with higher day 30 sCD30 levels (2.2 change in odds for an SD increase in tacrolimus AUC 0-12, P = 0.01; 5.5 change in odds for an SD increase in tacrolimus predose concentration, P < 0.0001). In contrast, MPA and total and free prednisolone exposures were not independently associated with sCD30 levels. CONCLUSIONS: The sCD30 levels are significantly reduced in the presence of combination immunosuppression but are differentially affected by different immunosuppressant agents. More research is required before introduction of sCD30 measurement into clinical practice can be considered.

Imbalance in serum soluble CD30/CD30L and CD40/CD40L systems are associated with ovarian tumors.

The aim of the study was to examine the concentrations of the soluble receptors and their ligands of CD30/CD30L and CD40/CD40L systems in the serum of women with ovarian tumor and in the ovarian cyst fluid of women with Cystadenoma serosum. The study included 120 women with ovarian tumors. As a control, sera were obtained from 60 healthy female volunteers. Concentrations of the sCD30, sCD30L, sCD40 and sCD40L in the serum and the ovarian cyst fluid were measured by ELISA enzyme-linked immunosorbent assay. Concentrations of both sCD30 and sCD30L in serum of women with ovarian tumors were significantly higher than in control (p < 0.0001). The highest serum receptor and its ligand levels were observed in women with ovarian cancer (p < 0.0001). Moreover, results showed significantly increased levels of sCD40 and sCD40L serum in women with ovarian tumors, as compared to the control group (p < 0.0001). The highest concentration of sCD40 in the serum of women with ovarian cancer and sCD40L in serum of women with Teratoma maturum (p < 0.0001) were observed. Impaired apoptosis among women with ovarian tumors is associated with the impairments of soluble CD30/CD30L and CD40/CD40L systems. Measurement of studied parameter concentrations in serum of women with ovarian tumors has been suggested to be a potential tool in monitoring of inflammatory. Evaluation of sCD30, sCD30L and sCD40 might be an early diagnostic marker in patients with the ovarian cancer. Concentrations of the studied parameters in the ovarian cyst fluid higher than the serum values suggest local suppression of the immune response. However, the final evaluation of the importance of measurement of serum levels of them requires further investigation.

CD30 ligand/CD30 interaction is involved in pathogenesis of inflammatory bowel disease.

BACKGROUND AND AIMS: Although CD30 has long been recognized as an important marker in many lymphomas of diverse origin, and as an activation molecule on B and T cells, its primary function has remained obscure. Soluble CD30 (sCD30) is released from CD30 on the cell membrane by enzymatic cleavage. This study investigated the role of CD30 ligand (CD30L)/CD30 signals in intestinal mucosal damage. METHODS: Serum sCD30 in patients with ulcerative colitis (UC) and Crohn's disease (CD) and healthy individuals was assessed. A model of enteritis induced by anti-CD3 monoclonal antibody injection was studied in wild-type mice and in CD30L knockout mice. RESULTS: Increased sCD30 was observed in UC and CD patients, and the level was correlated with disease activity in both conditions. In a murine model of enteritis, histological intestinal damage was significantly reduced in CD30L knockout mice with decreased Th1 and Th17 cytokine levels. Moreover, blocking of CD30L/CD30 signals by CD30-immunoglobulin (CD30-Ig) resulted in reduced inflammation. CONCLUSIONS: Increased sCD30 expression correlating with disease activity suggested that CD30L/CD30 signals play an important role in pathogenesis of UC and CD. CD30L/CD30 pathway acts as an accelerator of enteritis in a murine disease model. Successful blockade of enteritis by CD30-Ig suggests a potential tool for future therapy of inflammatory bowel diseases.

High soluble CD30, CD25, and IL-6 may identify patients with worse survival in CD30+ cutaneous lymphomas and early mycosis fungoides.

Histopathology alone cannot predict the outcome of patients with CD30+ primary cutaneous lymphoproliferative disorders (CD30CLPD) and early mycosis fungoides (MF). To test the hypothesis that serum cytokines/cytokine receptors provide prognostic information in these disorders, we measured soluble CD30 (sCD30), sCD25, and selected cytokines in cell cultures and sera of 116 patients with CD30CLPD and 96 patients with early MF followed up to 20 years. Significant positive correlation was found between sCD30 levels and sCD25, CD40L, IL-6, and IL-8, suggesting that CD30+ neoplastic cells secrete these cytokines, but not Th2 cytokines. In vitro studies confirmed that sCD30, sCD25, IL-6, and IL-8 are secreted by CD30CLPD-derived cell lines. CD30CLPD patients with above normal sCD30 and sCD25 levels had worse overall and disease-related survivals, but only sCD30 retained significance in Cox models that included advanced age. High sCD30 also identified patients with worse survival in early MF. Increased IL-6 and IL-8 levels correlated with poor disease-related survival in CD30CLPD patients. We conclude that (1) neoplastic cells of some CD30CLPD patients do not resemble Th2 cells, and that (2) high serum sCD30, sCD25, IL-6, and perhaps IL-8 levels may provide prognostic information useful for patient management.

Safety and tolerability of a modified filter-type device for leukocytapheresis using ACD-A as anticoagulant in patients with mild to moderately active ulcerative colitis. Results of a pilot study.

Cellsorba™ is a medical device for leukocytapheresis (LCAP) treatment of ulcerative colitis (UC). Cellsorba™ EX Global type has been developed from Cellsorba E for intended use with ACD-A as anticoagulant. We evaluated safety and efficacy of the modified Cellsorba using ACD-A in a pilot trial comprising patients with active UC, despite receiving 5-ASA. A total of 10 LCAP treatments/patients were administered. Safety assessment focused on clinical signs and symptoms, hematological variables, as well as levels of bradykinin and IL-6. Efficacy was determined using the Mayo clinical/endoscopic scoring index as well histological assessment of biopsies. Additional aim was to evaluate the impact of apheresis system lines and filter on selected regulatory molecules. All six subjects completed the trial without any serious adverse events. WBC, platelet counts, and levels of bradykinin and IL-6 were not significantly affected. The median Mayo score decreased from 8.0 to 3.5 at week 8 (and to 2 at week 16 for the responders). Four patients were responders, of whom two patients went into remission. Median histological scores decreased from 3.5 to 2.0 in these four patients. Concentration of LL-37 increased within the apheresis system lines. LCAP with Cellsorba EX using ACD-A as anticoagulant was found to be a safe and well-tolerated procedure in patients with active UC. The positive impact on efficacy parameters merits further evaluation in a controlled fashion.

CD153 in rheumatoid arthritis: detection of a soluble form in serum and synovial fluid, and expression by mast cells in the rheumatic synovium.

OBJECTIVE: A CD30-CD153 mast cell axis has been described in skin inflammations and Hodgkin's lymphoma. We investigated if a soluble form of CD153 is present in the serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA), and determined whether mast cells express CD153 in the synovium of these patients. METHODS: Soluble forms of CD30 and CD153 were quantified in serum and SF of patients with RA by ELISA. Consecutive sections of synovial biopsies from 12 patients were stained against tryptase (mast-cell marker), CD30, and CD153. RESULTS: Elevated concentrations of the soluble form of CD153 were found in serum from 14/15 RA patients. In the SF, 11/20 patients had detectable levels of soluble CD153. CD30 and CD153 were expressed in all biopsies that were studied. Mast cells were present in all the synovial biopsies, and expressed CD153 in one-third of the cases. CONCLUSION: We observed that CD153 was expressed in the synovium of patients with RA and we were able to correlate the serum levels of soluble CD153 with SF levels in the same patients. Because CD30 can activate mast cells to release chemokines without degranulation, our finding that mast cells express CD153 in RA synovium raises the possibility that a CD30-CD153 axis may contribute to the activation of synovial mast cells in the absence of degranulation.

Pre-transplant level of soluble CD30 is associated with infection after heart transplantation.

BACKGROUND: One immunologic element of the immune system is the CD30 molecule which belongs to the TNF-R superfamily. CD30 can serve as a T-cell signal transducing molecule and is expressed by a subset of activated T lymphocytes, CD45RO(+) memory T cells. Augmentation of soluble CD30 during kidney transplant (Tx) rejection has been reported. Our study was to determine if the level of sCD30 prior to heart transplant (HTx) could categorize the patients (pts) into high or low immunologic risk for post-Tx outcome. METHODS: Pre-Tx sera from 100 consecutive HTx recipients were studied. sCD30 was detected by ELISA using the commercially available CD30 monoclonal antibody. Level of sCD30 was correlated with two-yr Tx outcome. RESULTS: Significant correlation was seen between the high level of sCD30 and lower incidence of infection. Four of the 35 pts with pre-Tx high level of sCD30 level (>90 U/mL) developed infection post-Tx. However, 31/65 pts who had a low level of sCD30 (<90 U/mL) developed infection post-transplantation (p < 0.0003). No remarkable differences were noted with the other clinical parameters, including mean hospitalization, 3A biopsy rejection or death. CONCLUSIONS: We report for the first time that the high level of sCD30 prior to the HTx may be associated with a higher immunologic ability of the pts and therefore, may have a protective effect in the development of infection post-Tx.