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PubMed2004

Beryllium-induced tumor necrosis factor-alpha production by CD4+ T cells is mediated by HLA-DP.

Beryllium (Be) presentation to CD4+ T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4+ T cells undergo clonal proliferation and T-helper 1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti-HLA-DP, but not anti-HLA-DR, monoclonal antibody inhibited Be-stimulated TNF-alpha expression in lung CD3+ CD4+ T cells. This monoclonal antibody also blocked Be-specific T cell proliferation, increased production of TNF-alpha mature-mRNA transcripts, and increased TNF-alpha protein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated upregulation of TNF-alpha mature-mRNA levels with TNF-alpha protein production was a unique property of CBD BAL cells, and did not occur in BAL cells from Be-sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4+ T cells from CBD patients resulting in proliferation and proinflammatory cytokine production.

Antibodies, Monoclonal↗
PubMedDate not supplied

Chronic granulomatous pneumonia and lymphocytic responses induced by inhaled beryllium metal in A/J and C3H/HeJ mice.

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). Key to the pathogenesis of CBD is a delayed-type hypersensitivity reaction, in which Be most likely functions as a hapten and acts as a Class II-restricted antigen, stimulating local proliferation and accumulation in the lung of Be-specific CD4+ T cells. The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2a) mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro. Responses were similar in both strains of mice. The lungs of all Be-exposed mice had interstitial compact aggregates of lymphocytes, and granulomatous pneumonia characterized by vacuolated macrophages and giant cells in alveoli, neutrophils in alveoli and alveolar septa, multifocal interstitial granulomas, and interstitial infiltrates of lymphocytes, plasma cells, monocytes, and macrophages. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO4 in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans' giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease.

Administration, Inhalation↗
PubMedDate not supplied

Role of the HLA-DP Glu 69 and the TNF-alpha TNF-alpha 2 gene markers in susceptibility to beryllium hypersensitivity.

Berylliosis is an environmental chronic inflammatory disorder of the lung caused by inhalation of beryllium dusts, characterized by the accumulation of CD4+ T cells and macrophages in the lower respiratory tract. Beryllium presentation to CD4+ T cells from patients with berylliosis results in T cell activation and these Be-specific CD4+ T cells undergo clonal proliferation and Th1-type cytokine production such as interleukin-2, interferon-gamma and tumor necrosis factor-alpha. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with major histocompatibility gene and the TNF-alpha gene. The HLA-DP glutamic 69 residue was shown to be the MHC genetic marker associated with disease susceptibility; furthermore the TNF-alpha TNFA-308*2 allele was found to be independently associated with HLA-DP Glu69 in the determination of berylliosis risk.

Alleles↗
PubMed2002

HLA-DP-unrestricted TNF-alpha release in beryllium-stimulated peripheral blood mononuclear cells.

Berylliosis is a granulomatous disorder of the lung caused by inhalation of beryllium (Be) and dominated by the accumulation of CD4+ T-helper (Th)1 memory T-cells proliferating in response to Be in the lower respiratory tract. Two gene markers have been associated with susceptibility to berylliosis: 1) the human leucocyte antigen (HLA)-DP gene whose allelic variants, carrying glutamate in position 69 of the beta-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)-gamma releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)-alpha which has been shown to increase berylliosis risk independent of HLA-DPGlu69. In order to determine whether TNF-alpha release was triggered by Th1 T-cell activation by Be stimulation in the context of HLA-DPGlu69 molecules, the proliferation of BeSO4-stimulated blood mononuclear cells and the release of IFN-gamma, TNF-alpha, RANTES (regulated on activation normal T-cell expressed and secreted), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4, IL-6, IL-8, IL-10 and IL-12 by BeSO4-stimulated blood mononuclear cells was quantified in 11 individuals with berylliosis using an anti-HLA-DP antibody as a probe for HLA-DP restricted T-cell activation. While proliferation and IFN-gamma release were completely abrogated by HLA-DP inhibition (inhibition with anti-HLA-DP monoclonal antibody (mAb): 88+/-16 and 77+/-16%, respectively; anti-HLA-DR: 29+/-38 and 14+/-10%, respectively), the release of TNF-alpha was not (inhibition with anti-HLA-DP mAb: 8.9+/-7.8%). No other cytokine was detected at significant levels. Moreover, Be was able to induce TNF-alpha production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN-gamma production. In conclusion, these data suggest that the tumour necrosis factor-alpha response of mononuclear cells is independent of the activation of beryllium-specific human leucocyte anitgen-DP restricted T-cells, which is consistent with the finding that the tumour necrosis factorA2 and the human leucocyte anitgen-DPGlu69 genetic markers are independently interacting in increasing berylliosis risk.

Adult↗
PubMed2001

Indirect and direct gas exchange at maximum exercise in beryllium sensitization and disease.

STUDY OBJECTIVES: To determine whether pulse oximetry accurately estimates arterial blood gas measurements during exercise in the assessment of chronic beryllium disease (CBD) and beryllium sensitization (BeS). DESIGN: Participants underwent maximal exercise physiology testing in a clinical-practice setting. Oxygen saturation in the blood was measured through an indwelling arterial line and by pulse oximetry. SETTING: All exercise physiology tests were performed in the pulmonary physiology unit of the National Jewish Medical and Research Center (NJMRC) between December 1985 and November 1998. PATIENTS: We analyzed the exercise physiology data for 168 individuals who were referred to NJMRC for evaluation of possible CBD and underwent exercise testing. On evaluation, they subsequently received diagnoses of either CBD or BeS. RESULTS: In BeS subjects, the percentage of oxygen saturation as measured by pulse oximetry (SpO(2)) often underestimated the percentage of arterial oxygen saturation (SaO(2)) (mean [+/- SD] underestimation, 0.88 +/- 4.6%) at maximum exercise and showed no significant correlation (r = -0.13; p = 0.3). The use of SpO(2) misclassified 14.9% of BeS subjects as having abnormal gas exchange levels (< 90%) that were normal by arterial blood gas measurement. In contrast, SpO(2) and SaO(2) values correlated at maximum exercise in CBD subjects (r = 0.55 [corrected]; p = 0.0001) without exhibiting SpO(2) underestimation of SaO(2), and misclassification occurred in only 5.9%. CONCLUSIONS: These data suggest that pulse oximetry cannot be used reliably to distinguish between CBD and BeS and, thus, is not an adequate substitute for arterial blood gas analysis with exercise.

Adult↗
PubMed1983

[Studies on the cell-mediated immunity caused by beryllium compounds].

In order to examine the sensitizing ability of beryllium (Be), a footpad reaction test and a macrophage migration inhibition test were carried out using mice treated with beryllium compounds. The findings of the experiments are summarized as follows: 1) The footpad reaction test of the mice injected with BeCl2 once a week subcutaneously at their dorsal area showed the positive results after four injections. The macrophage migration inhibition test was also performed by an agarose plate method using peritoneal cells and spleen cells obtained from these mice. The ratio of the number of positive mice showed more than 50% after five injections when peritoneal cells were used and after six injections when spleen cells were used. 2) The footpad reaction test of mice injected with one of various Be-compounds six times once a week showed a cross positive reaction against these compounds, and the macrophage migration of these mice was inhibited by these Be-compounds, but not by other metals. 3) When mice were once injected with 7BeCl2, about a half dose of the injected metal was discharged from the body within 7 days after the injection, and about a half dose of the residual metal was still found in the injected site. Further investigations may be required to solve the point that the persistent remaining of this metal in situ may raise the Be sensitizing ability.

Animals↗
PubMed1983

[Studies on the effects of beryllium oxide in purity and fired temperature to the occurrence of chronic pulmonary berylliosis].

Among various beryllium (Be) compounds, beryllium oxide (BeO) has so far been noted as a causative substance which introduce chronic pulmonary berylliosis. In our study, chronic pulmonary berylliosis was experimentally evoked by using two species of BeO with individual purity and fired temperature (A group: 95.0% in purity, and 1,300 degrees C or above in fired temperature, B group: 99.9% in purity, and 800-1,000 degrees C in fired temperature), and demarcation of prepared Be concentration involving in the genesis of the disorder was examined. BeO with various concentrations ranging from 200 micrograms to 0.1 micrograms were mixed with 0.1% agar solution and infused into right thorax cavity of male guinea pig, following which variation of the body weight was checked and pulmonary histo-pathological findings, peripheral hematological tests, and sero-biochemical tests were carried out on a periodical basis at 8 weeks, 16 weeks, and 32 weeks. The results obtained are outlined herein. 1) Body weights of test animals in both A group and B group were significantly decreased as compared with that of the control. 2) Pulmonary histo-pathological findings revealed the genesis of epitheloid-cell granuloma in the lungs where non-infusion sides were included, which resembled to non-caseating granuloma in the human pulmonary berylliosis. 3) The frequency in the genesis of epithelaid-cell granuloma was 1/36 (2.8%) in A group and 4/35 (11.4%) in B group, granuloma formation being marked in the latter. 4) Examination of the frequency in terms of BeO dosages revealed no results suggesting the dose-response relationship between pulmonary granuloma formation and the dosage. 5) There were no changes worthy of note in peripheral hematological tests. 6) Sero-biochemical tests revealed that alkaline phosphatase value together with total protein in each was significantly decreased in B group at 32 weeks following the infusion.

Berylliosis↗
PubMed1987

[Immunological study of beryllium workers].

Immunological health surveys of Beryllium (Be) workers in a copper-beryllium casting factory were made 10 times during the 5-year period from 1981 to 1985. The total number of Be workers was 150. 1) Macrophage migration inhibition test was performed by an agarose plate method using Be as antigen with peritoneal cells from guinea pigs and small amounts of Be worker's blood. We found that 1 out of 22 healthy Be workers (4.5%) that migration index (MI) was below 80% after 24 h and 5 (22.7%) after 48 h. The mean of MI in Be workers showed significant low value as compared with that of the control group (p less than 0.01). 2) It was found that the serum complement titer tended to be lower in Be workers than in the control group. The serum complement titer of 3 to 6 subjects showed to be less than 30 U/ml every survey. 3) Although a few showed the abnormal levels in serum immunoglobin (IgG, IgA and IgE), the means of these immunoglobin levels were not markedly changed and they were in the normal ranges, respectively. 4) MI values significantly correlated with IgE level in Be workers, that is y= -8.9 x + 997.8 (r = -0.473, p less than 0.05). These results suggest that macrophage migration inhibition test and serum complement titer were of value for assaying of sensitivity to Be and immune responses in Be workers.

Beryllium↗
PubMed1982

Comparison of neutron therapy beams produced by 50 MeV deuterons and 65 MeV protons on beryllium.

Neutron beams produced by bombarding a 10 cm thick beryllium target with 50 MeV deuterons have been used at Louvain-la-Neuve since nearly 4 years for routine therapeutic applications. At the end of 1981 they were replaced by neutron beams produced by 65 MeV protons on beryllium, mainly in order to improve the beam penetration in tissues. However, produced of neutrons from the p leads to Be reaction implies some disadvantages, mainly a lower dose rate and a higher activation level. In order to solve the problem a new target configuration was designed, consisting of a remote handled system which permits the use of 2 different target assemblies. The irradiated target is automatically removed immediately after the irradiation which greatly protects against exposure to the staff. The dosimetric characteristics of the d(50)-Be and p(65)-Be neutrons beams are compared.

Beryllium↗
PubMed2001

Carcinogenic potential and genomic instability of beryllium sulphate in BALB/c-3T3 cells.

Occupational exposure to beryllium (Be) and Be compounds occurs in a wide range of industrial processes. A large number of workers are potentially exposed to this metal during manufacturing and processing, so there is a concern regarding the potential carcinogenic hazard of Be. Studies were performed to determine the carcinogenic potential of beryllium sulfate (BeSO4) in cultured mammalian cells. BALB/c-3T3 cells were treated with varying concentrations of BeSO4 for 72 h and the transformation frequency was determined after 4 weeks of culturing. Concentrations from 50-200 microg BeSO4/ml, caused a concentration-dependent increase (9-41 fold) in transformation frequency. Non-transformed BALB/c-3T3 cells and cells from transformed foci induced by BeSO4 were injected into both axillary regions of nude mice. All ten Be-induced transformed cell lines injected into nude mice produced fibrosarcomas within 50 days after cell injection. No tumors were found in nude mice receiving non-transformed BALB/c-3T3 cells 90 days post-injection. Gene amplification was investigated in K-ras, c-myc, c-fos, c-jun, c-sis, erb-B2 and p53 using differential PCR while random amplified polymorphic DNA fingerprinting was employed to detect genomic instability. Gene amplification was found in K-ras and c-jun, however no change in gene expression or protein level was observed in any of the genes by Western blotting. Five of the 10 transformed cell lines showed genetic instability using different random primers. In conclusion, these results indicate that BeSO4 is capable of inducing morphological cell transformation in mammalian cells and that transformed cells induced by BeSO4 are potentially tumorigenic. Also, cell transformation induced by BeSO4 may be attributed, in part, to the gene amplification of K-ras and c-jun and some BeSO4-induced transformed cells possess neoplastic potential resulting from genomic instability.

3T3 Cells↗
PubMed2002

Beryllium induces apoptosis in human lung macrophages.

The link between metal-induced apoptosis and granulomatous inflammation in human disease pathogenesis is not established. The presence of TUNEL positive nuclei in chronic beryllium disease (CBD) pulmonary granulomas suggested the possibility that beryllium (Be) could induce apoptosis in adherent macrophages from CBD bronchoalveolar (BAL) cells. Apoptosis was measured in un-stimulated and Be-stimulated BAL adherent macrophages from CBD (n = 21) and Be-sensitized (BeS, n = 16) subjects. Be-stimulated CBD and BeS macrophages underwent caspase-dependent nuclear fragmentation, cytoplasmic membrane blebbing and CD14 loss. Be-stimulated adherent macrophage apoptosis was not due to TNF-alpha production. Apoptosis, CD14 loss and TNF-alpha production were not observed in unstimulated BAL macrophages. Thus, Be-stimulated BAL adherent macrophage apoptosis occurred whether cells were derived from patients with granulomatous inflammation or not, was caspase-mediated and occurred independent of TNF-alpha levels. We conclude that Be-induced human lung adherent macrophage apoptosis could contribute to the host's continued re-exposure to Be resulting in chronic granulomatous inflammation.

Apoptosis↗
PubMed1975

[Effect of a beryllium complex on growth of Pseudomonas fluorescens (types R and S). II. Competition with magnesium].

A study of the inhibitory action of beryllium on the growth of Pseudomonas fluorescens reveals that the observed effect can be partly explained by competition between beryllium and magnesium in various processes which are indispensable to cellular metabolism. In addition, an "adaptation" phenomenon is observed which appears to be based on the selection of cells which are more highly resistant towards the inhibitor.

Beryllium↗
PubMed2001

[Determination of beryllium in atmospheric particulate by graphite furnace atomic absorption spectrophotometer using aluminium as a matrix modifier agent sampling with micropore filter membrane].

Beryllium in the atmospheric particulates is collected with 0.22 micron pore diameter micropore filter membrane, which is determined by graphite furnace atomic absorption spectrophotometer using aluminium as a matrix modifier agent. This sampling method shown several advantages: easy, complete and fast digestion; low membrane blank; high elution recovery, standard addition recovery, precision and accuracy. The addition of 800 mg.L-1 aluminium to beryllium solution allows ashing temperature of 2,000 degrees C. The detection limit of 13.5 ng was obtained.

Air Pollutants↗
PubMed2004

Radiation dosimetry of a graphite moderated radium-beryllium source.

The Brookhaven National Laboratory Sigma Pile is a radium-beryllium neutron source imbedded in a cube of graphite blocks. The pile is approximately 2.13 m on four sides and is 3.07 m high. Thermoluminescent dosimeters were used to determine the neutron and gamma-ray dose rates in the pile. Gamma-ray dose rate measurements have also been made in the air outside of the pile, while the radium-beryllium neutron source was being withdrawn from the pile. The Monte Carlo code has been used to calculate the coupled neutron-photon transport. Measured dose rates at various locations agreed with the calculated values within 5% to 15%.

Algorithms↗
PubMed1992

Characterization of the aluminum and beryllium fluoride species which activate transducin. Analysis of the binding and dissociation kinetics.

Aluminofluoride and beryllofluoride complexes can activate the heterotrimeric G-proteins by binding next to GDP in the nucleotide site of their G alpha subunit and acting as analogs of the gamma-phosphate of a GTP. However, the exact structures of the activatory complexes in solution as well as those of the bound complexes in the nucleotide site are still disputed. We have studied, by monitoring the activation-dependent tryptophan fluorescence of transducin T alpha subunit, the pF (-log[F-]) and pH dependencies of the kinetics of activation and deactivation of T alpha GDP in the presence of NaF and aluminum or beryllium salts. Comparisons were made with the calculated pF and pH dependencies of the distribution of the metallofluoride complexes, in order to identify the activating species. We observed that the contribution of a magnesium-dependent mechanism of activation by fluoride (Antonny, B., Bigay, J., and Chabre, M. (1990) FEBS Lett. 268, 277-280) and effects due to slow equilibration kinetics between various aluminofluoride complexes could give rise to puzzling kinetics that had caused misinterpretations of previous results. Once corrected for these effects, our results suggest that with aluminum AlF3(OH)- is, rather than AlF4-, the main activating species and that the bound form of the complex is tetracoordinated GDP-AlF3. Deactivation kinetics depend on the free fluoride concentration in the medium, suggesting that the simple bimolecular scheme: T alpha GDP-AlF3 in equilibrium with T alpha GDP+AlF3(OH) does not fully describe the interaction. Fluorides in the bound complexes can also exchange with free F- ions in solution. With beryllium, two complexes are activatory: BeF3-.H2O and BeF2(OH)-.H2O. In the nucleotide site these give two tetracoordinated complexes, GDP.BeF3 and GDP.BeF2(OH), as shown by their different dissociation rates.

Aluminum↗
PubMedDate not supplied

[An evaluation of the DNA-damaging action of the metal carcinogen beryllium using a bacterial repair test].

Using four strains of E. coli with different DNA repairing capacities it was established that beryllium efficacy in the DNA repair test (extension inhibition zone and the lowest concentration inhibiting bacterial growth) depended on pH of the medium and the cation, anion concentration and the metal acted bacteriostatically. A conclusion was made that in the given case the repair test detected the nonidentified membrane function of the DNA repair system, possibly associated with the usage of exogenous orthophosphate rather than the repair synthesis in response to DNA damage by beryllium.

Bacteriological Techniques↗
PubMed1977

Histogenesis of beryllium-induced bone tumours.

In response to beryllium treatment, irregular bone formation starts mainly in the marrow cavity of long bones, preceding neoplastic growth. Irregular medullary bone formation may be connected with the endosteum, but usually it develops in the bone marrow, independently of the endosteum. Osteogenesis in the bone marrow may be preceded by fibrosis but irregular bone may be formed also without any previous histological changes in the bone marrow. The tumour develops directly from the medullary bone. The prolonged irritation causes abnormal osteogenesis, which ultimately turns into neoplastic proliferation. Thus, the beryllium-induced bone sarcoma is, from histogenesis point of view, a hyperplaseogenic tumour. Irregular bone formation is considered a preblastomatous change, because it is closely connected with the development of the tumour and precedes it in time. The multiplicity of the tumour is explained by the "neoplastic field" theory of WILLIS.

Animals↗