Increased serum anti-CYP2E1 IgG autoantibody levels may be involved in the pathogenesis of occupational trichloroethylene hypersensitivity syndrome: a case-control study.

Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case-control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.

Increased risk of occupational trichloroethylene hypersensitivity syndrome at exposure levels higher than 15 mg/L of urinary trichloroacetic acid, regardless of whether the patients had the HLA-B*13:01 allele.

Occupational trichloroethylene (TCE) exposure can cause hypersensitivity syndrome (TCE-HS). The human leukocyte antigen (HLA)-B*13:01 is reportedly an important allele involved in TCE-HS onset. However, the threshold exposure level causing TCE-HS in relation to HLA-B*13:01 remains unknown. We conducted a case-control study comprising 37 TCE-HS patients and 97 age- and sex-matched TCE-tolerant controls from the Han Chinese population. Urine and blood of patients were collected on the first day of hospitalization, and those of controls were collected at the end of their shifts. Urinary trichloroacetic acid (TCA) was measured as an exposure marker, and end-of-shift levels in the patients were estimated using the biological half-life of 83.7 h. HLA-B genotype was identified using DNA from blood. Crude odds ratios (ORs) for TCE-HS in the groups with urinary TCA concentration >15 mg/L to ≤50 mg/L and of >50 mg/L were 21.9 [95% confidence interval (CI) 4.2-114.1] and 27.6 (6.1-125.8), respectively, when the group with urinary TCA ≤15 mg/L was used as a reference. The frequency of HLA-B*13:01, the most common allele in the patients, was 62.2% (23/37), which was significantly higher than 17.5% (17/97) in the TCE-tolerant controls, with a crude OR of 8.4 (3.1-22.6). The mutually-adjusted ORs for urinary TCA >15 to ≤50 mg/L, >50 mg/L, and for HLA-B*13:01 were 33.4 (4.1-270.8), 34.0 (5.3-217.1), and 11.0 (2.4-50.7), respectively. In conclusion, reduction of TCE exposure to ≤15 mg/L is required for TCE-HS prevention because urinary TCA concentration >15 mg/L showed increased risk of TCE-HS, regardless of whether the patients had the HLA-B*13:01 allele.

Exposure reconstruction of trichloroethylene among patients with occupational trichloroethylene hypersensitivity syndrome.

Occupational trichloroethylene (TCE) exposure can induce life-threatening generalized dermatitis accompanied by hepatitis: TCE hypersensitivity syndrome (HS). Since the patients' exposure levels have not been fully clarified, this study estimated end-of-shift urinary concentrations of trichloroacetic acid (TCA) and their lower limit below which the disease occurrence was rare. TCA concentration was measured in 78 TCE HS patients whose urine was collected at admission between 2nd and 14th d after their last shift. Then a linear regression model was used to calculate the mean TCA concentration with 95% confidence interval (95% CI) and 95% prediction interval (95% PI) in the end-of-shift urine. The estimated mean concentration was 83 (95% CI, 49-140) mg/l with 95% PI 9.6-720 mg/l. TCA concentrations were also measured in the end-of-shift urine of 38 healthy workers involved in the same job as were the patients. The geometric mean and its 95% CI were 127 mg/l and 16-984 mg/l, respectively. The exposure levels in HS patients might have thus overlapped with those in workers without HS. Accordingly, it was suggested that HS occurred in the environment where the workers were exposed to the TCE concentration corresponding to the urinary TCA concentration as low as 10 mg/l.

Follow-up assessment of two cases of trichloroethylene hypersensitivity syndrome: A case report.

The present study aimed to explore the stability, curability and sequelae of cases of Trichloroethylene (TCE) Hypersensitivity Syndrome (THS), and to investigate the causal allergens of THS. Two cases of THS were followed-up in the current study; both cases were healing following glucocorticoid therapy and were discharged >10 weeks prior to follow-up. A questionnaire investigation, health examination and patch test were performed. Allergens of TCE and its metabolites, including chloral hydrate, trichloroethanol (TCOH) and trichloroacetic acid, were applied in the patch test; 4 controls were included. The two subjects were experiencing itching, pigmentation and xerosis of the skin, and had abnormal results in the ophthalmology Schirmer I test and tear break-up time. The body temperature, liver function, superficial lymph nodes, blood, urine routine and autoimmune antibodies of two subjects were shown to be normal, and no new rashes had appeared. All mass concentration of chloral hydrate and TCOH were positive; 5.0% trichloroacetic acid was weakly positive, 0.5% trichloroacetic acid and all mass concentration of TCE were negative. All patch tests were negative in the 4 control subjects. The results suggest that THS was stable following treatment with glucocorticoid therapy. Dry eye syndrome may continue as a sequelae of THS. The patch test demonstrated that the mechanism underlying THS is delayed-type hypersensitivity induced by TCE. In addition, as the hypersensitivity state in a THS rehabilitee could be sustained over a long period of time, it suggests that the metabolites of TCE, not TCE itself, are responsible for THS. Therefore, patients with THS should avoid contact with TCE and its metabolites, and avoid using hypnotic and anticonvulsive drugs containing chloral hydra as the primary ingredient.

Occupational trichloroethylene hypersensitivity syndrome: human herpesvirus 6 reactivation and rash phenotypes.

BACKGROUND: Trichloroethylene (TCE) is an industrial solvent which can cause severe generalized dermatitis, i.e., occupational TCE hypersensitivity syndrome. Reactivation of latent human herpesvirus 6 (HHV6) can occur in such patients, which has made TCE known as a causative chemical of drug-induced hypersensitivity syndrome (DIHS). OBJECTIVE: This study aimed to clarify HHV6 status, cytokine profiles and their association with rash phenotypes in patients with TCE hypersensitivity syndrome. METHODS: HHV6 DNA copy numbers, anti-HHV6 antibody titers, and cytokines were measured in blood prospectively sampled 5-7 times from 28 hospitalized patients with the disease. RESULTS: The patients (19 had exfoliative dermatitis (ED) and 9 had non-ED type rash) generally met the diagnostic criteria for DIHS. Viral reactivation defined as increases in either HHV6 DNA (≥100 genomic copies/10(6) peripheral blood mononuclear cells) or antibody titers was identified in 24 (89%) patients. HHV6 DNA, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-5, IL-6 and IL-10 concentrations were remarkably higher in the patients than in the healthy workers (p<0.01). Positive correlations between HHV6 DNA, TNF-α, IFN-γ, IL-6 and IL-10 were significant (p<0.05) except for that between HHV6 DNA and IFN-γ. An increase in HHV6 DNA was positively associated with an increase in TNF-α on admission (p<0.01). HHV6 DNA, the antibody titers, TNF-α and IL-10 concentrations were significantly higher in ED than in the non-ED type (p<0.05). CONCLUSION: Reactivated HHV6 and the increased cytokines could be biomarkers of TCE hypersensitivity syndrome. The higher-level reactivation and stronger humoral responses were associated with ED-type rash.

Upregulation of calprotectin and downregulation of retinol binding protein in the serum of workers with trichloroethylene-induced hypersensitivity dermatitis.

OBJECTIVES: The aim of this study was to explore the involved pathophysiological processes and develop biomarkers of trichloroethylene-induced hypersensitivity dermatitis (THD). METHODS: We examined the impact of THD on the serum proteome in 8 male patients by comparing the serum samples between acute and healed stages. Sample pooling and immunodepletion were applied for sample preparation. Two-dimensional gel electrophoresis coupled with matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-TOF/MS) was utilized to identify and quantitate differentially expressed proteins. Changes in selected proteins were further confirmed by an ELISA assay. RESULTS: A total of 41 spots were quantitated with significant alteration (p<0.05; fold-change≥± 3.0) in the serum between the acute and healed stages. Of these proteins, 26 proteins were identified by MALDI-TOF-TOF/MS. The identified proteins could be categorized into diverse functional classes, e.g., immunity and defense response, vitamin and lipid transport, fatty acid biosynthesis, actin binding, proteolysis and glycolysis. The ELISA assay confirmed the relative upregulation of calprotectin (S100A8/A9) and downregulation of retinol binding protein (RBP4) in the serum of the acute stage. The alteration of calprotectin and RBP4 was found to be specific to THD rather than trichloroethylene exposure. CONCLUSIONS: The pathophysiological processes underlying THD may involve elevated inflammatory responses and oxidative stress, inhibition of vitamin transport, depression of fatty acid biosynthesis, loss of extracellular actin scavenger, increase in oxygen transport, dysfunction in lipid transport, proteolysis and glycolysis. The combination of higher calprotectin and lower RBP4 levels in the serum could be used as potential biomarkers of THD.

iTRAQ-based proteomic profiling of human serum reveals down-regulation of platelet basic protein and apolipoprotein B100 in patients with hematotoxicity induced by chronic occupational benzene exposure.

Benzene is an important industrial chemical and an environmental contaminant, but the pathogenesis of hematotoxicity induced by chronic occupational benzene exposure (HCOBE) remains to be elucidated. To gain an insight into the molecular mechanisms and developmental biomarkers for HCOBE, isobaric tags for relative and absolute quantitation (iTRAQ) combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) were utilized. Identification and quantitation of differentially expressed proteins between HCOBE cases and healthy control were thus made. Expressions of selected proteins were confirmed by western blot and further validated by ELISA. A total of 159 unique proteins were identified (≥95% confidence), and relative expression data were obtained for 141 of these in 3 iTRAQ experiments, with fifty proteins found to be in common among 3 iTRAQ experiments. Plasminogen (PLG) was found to be significantly up-regulated, whereas platelet basic protein (PBP) and apolipoprotein B100 (APOB100) were significantly down-regulated in the serum of HCOBE cases. Additionally, the altered proteins were associated with the molecular functions of binding, catalytic activity, enzyme regulator activity and transporter activity, and involved in biological processes of apoptosis, developmental and immune system process, as well as response to stimulus. Furthermore, differential expressions of PLG, PBP and APOB100 were confirmed by western blot, and the clinical relevance of PBP and APOB100 with HCOBE was validated by ELISA. Overall, our results showed that lowered expression of PBP and APOB100 proteins served as potential biomarkers of HCOBE, and may play roles in the benzene-induced immunosuppressive effects and disorders in lipid metabolism.