Differential susceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles. (1/92)

Chronic beryllium disease (CBD) is associated with the allelic substitution of a Glu69 in the HLA-DPB1 gene. Although up to 97% of CBD patients may have the Glu69 marker, about 30-45% of beryllium-exposed, unaffected individuals carry the same marker. Because CBD occurs in only 1-6% of exposed workers, the presence of Glu69 does not appear to be the sole genetic factor underlying the disease development. Using two rounds of direct automated DNA sequencing to precisely assign HLA-DPB1 haplotypes, we have discovered highly significant Glu69-containing allele frequency differences between the CBD patients and a beryllium-exposed, nondiseased control group. Individuals with DPB1 Glu69 in both alleles were almost exclusively found in the CBD group (6/20) vs the control group (1/75). Whereas most Glu69 carriers from the control group had a DPB1 allele *0201 (68%), most Glu69 carriers from the CBD group had a non-*0201 DPB1 Glu69-carrying allele (84%). The DPB1 allele *0201 was almost exclusively (29/30) associated with DPA1 *01 alleles, while the non-*0201 Glu69-containing DPB1 alleles were closely associated with DPA1 *02 alleles (26/29). Relatively rare Glu69-containing alleles *1701, *0901, and *1001 had extremely high frequencies in the CBD group (50%), as compared with the control group (6.7%). Therefore, the most common Glu69-containing DPB1 allele, *0201, does not seem to be a major disease allele. The results suggest that it is not the mere presence of Glu69, per se, but specific Glu69-containing alleles and their copy number (homozygous or heterozygous) that confer the greatest susceptibility to CBD in exposed individuals.  (+info)

Partial IL-10 inhibition of the cell-mediated immune response in chronic beryllium disease. (2/92)

Chronic beryllium disease (CBD) provides a human disorder in which to study the delayed type IV hypersensitivity response to persistent Ag that leads to noncaseating pulmonary granuloma formation. We hypothesized that, in CBD, failure of IL-10 to modulate the beryllium-specific, cell-mediated immune response would result in persistent, maximal cytokine production and T lymphocyte proliferation, thus contributing to the development of granulomatous lung disease. To test this hypothesis, we used bronchoalveolar lavage cells from control and CBD subjects to evaluate the beryllium salt-specific production of endogenous IL-10 and the effects of exogenous human rIL-10 (rhIL-10) on HLA expression, on the production of IL-2, IFN-gamma, and TNF-alpha, and on T lymphocyte proliferation. Our data demonstrate that beryllium-stimulated bronchoalveolar lavage cells produce IL-10, and the neutralization of endogenous IL-10 does not increase significantly cytokine production, HLA expression, or T lymphocyte proliferation. Second, the addition of excess exogenous rhIL-10 partially inhibited the beryllium-stimulated production of IL-2, IFN-gamma, and TNF-alpha; however, we measured no change in T lymphocyte proliferation or in the percentage of alveolar macrophages expressing HLA-DP. Interestingly, beryllium salts interfered with an IL-10-stimulated decrease in the percentage of alveolar macrophages expressing HLA-DR. We conclude that, in the CBD-derived, beryllium-stimulated cell-mediated immune response, low levels of endogenous IL-10 have no appreciable effect; exogenous rhIL-10 has a limited effect on cytokine production and no effect on T lymphocyte proliferation or HLA expression.  (+info)

Chronic beryllium disease and cancer risk estimates with uncertainty for beryllium released to the air from the Rocky Flats Plant. (3/92)

Beryllium was released into the air from routine operations and three accidental fires at the Rocky Flats Plant (RFP) in Colorado from 1958 to 1989. We evaluated environmental monitoring data and developed estimates of airborne concentrations and their uncertainties and calculated lifetime cancer risks and risks of chronic beryllium disease to hypothetical receptors. This article discusses exposure-response relationships for lung cancer and chronic beryllium disease. We assigned a distribution to cancer slope factor values based on the relative risk estimates from an occupational epidemiologic study used by the U.S. Environmental Protection Agency (EPA) to determine the slope factors. We used the regional atmospheric transport code for Hanford emission tracking atmospheric transport model for exposure calculations because it is particularly well suited for long-term annual-average dispersion estimates and it incorporates spatially varying meteorologic and environmental parameters. We accounted for model prediction uncertainty by using several multiplicative stochastic correction factors that accounted for uncertainty in the dispersion estimate, the meteorology, deposition, and plume depletion. We used Monte Carlo techniques to propagate model prediction uncertainty through to the final risk calculations. We developed nine exposure scenarios of hypothetical but typical residents of the RFP area to consider the lifestyle, time spent outdoors, location, age, and sex of people who may have been exposed. We determined geometric mean incremental lifetime cancer incidence risk estimates for beryllium inhalation for each scenario. The risk estimates were < 10(-6). Predicted air concentrations were well below the current reference concentration derived by the EPA for beryllium sensitization.  (+info)

Association of man-made mineral fibre exposure and sarcoidlike granulomas. (4/92)

It is assumed that sarcoidosis is caused by inhalation of air borne agents in susceptible persons triggering the inflammatory reaction. The association of metallic dust exposure, such as beryllium and aluminium, and sarcoidlike pulmonary disorders is well known. The ability of man-made mineral fibres (MMMF) to cause granulomatous lung disease has not been appreciated until now. Recently, we observed the association of sarcoidlike granulomatous reaction and occupational history of glass fibre exposure. We hypothesized that there might be a relationship between MMMF exposure and the development of sarcoidlike granulomas. Therefore, the records of 50 sarcoidosis patients-who visited our outpatient clinic between 1996 and 1999 were reviewed. This revealed that 14 cases recalled a history of exposure to either glass fibres or rock wool, both MMMF fibres. The available obtained tissue specimens (n = 12) were reviewed. In six cases electron microscopy qualitative analysis of small fragments of the tissue revealed among others silica, aluminium and sometimes titanium. A distinct relation between fibre deposits fibre deposits and granulomas was found. These findings indicate that in susceptible people MMMF exposure might be related to a chronic granulomatous disease similar to chronic beryllium disease.  (+info)

Government laboratory worker with lung cancer: comparing risks from beryllium, asbestos, and tobacco smoke. (5/92)

Occupational medicine physicians are frequently asked to establish cancer causation in patients with both workplace and non-workplace exposures. This is especially difficult in cases involving beryllium for which the data on human carcinogenicity are limited and controversial. In this report we present the case of a 73-year-old former technician at a government research facility who was recently diagnosed with lung cancer. The patient is a former smoker who has worked with both beryllium and asbestos. He was referred to the University of California, San Francisco, Occupational and Environmental Medicine Clinic at San Francisco General Hospital for an evaluation of whether past workplace exposures may have contributed to his current disease. The goal of this paper is to provide an example of the use of data-based risk estimates to determine causation in patients with multiple exposures. To do this, we review the current knowledge of lung cancer risks in former smokers and asbestos workers, and evaluate the controversies surrounding the epidemiologic data linking beryllium and cancer. Based on this information, we estimated that the patient's risk of lung cancer from asbestos was less than his risk from tobacco smoke, whereas his risk from beryllium was approximately equal to his risk from smoking. Based on these estimates, the patient's workplace was considered a probable contributing factor to his development of lung cancer.  (+info)

Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. (6/92)

Chronic beryllium disease results from beryllium exposure in the workplace and is characterized by CD4(+) T cell-mediated inflammation in the lung. Susceptibility to this disease is associated with particular HLA-DP alleles. We isolated beryllium-specific T cell lines from the lungs of affected patients. These CD4(+) T cell lines specifically responded to beryllium in culture in the presence of antigen-presenting cells that expressed class II MHC molecules HLA-DR, -DQ, and -DP. The response to beryllium was nearly completely and selectively blocked by mAb to HLA-DP. Additional studies showed that only certain HLA-DP alleles allowed presentation of beryllium. Overall, the DP alleles that presented beryllium to disease-specific T cell lines match those implicated in disease susceptibility, providing a mechanism for this association. Based on amino acid residues shared by these restricting and susceptibility DP alleles, our results provide insight into the residues of the DP beta-chain required for beryllium presentation.  (+info)

HLA-DP allele-specific T cell responses to beryllium account for DP-associated susceptibility to chronic beryllium disease. (7/92)

Occupational exposure to small molecules, such as metals, is frequently associated with hypersensitivity reactions. Chronic beryllium (Be) disease (CBD) is a multisystem granulomatous disease that primarily affects the lung, and occurs in approximately 3% of individuals exposed to this element. Immunogenetic studies have demonstrated a strong association between CBD and possession of alleles of HLA-DP containing glutamic acid (Glu) at position 69 in the HLA-DP beta-chain. T cell clones were raised from three patients with CBD in whom exposure occurred 10 and 30 years previously. Of 25 Be-specific clones that were obtained, all were restricted by HLA-DP alleles with Glu at DP beta69. Furthermore, the proliferative responses of the clones were absolutely dependent upon DP beta Glu(69) in that a single amino acid substitution at this position abolished the response. As befits a disease whose pathogenesis involves a delayed type hypersensitivity response, the large majority of Be-specific clones secreted IFN-gamma (Th1) and little or no IL-4 (Th2) cytokines. This study provides insights into the molecular basis of DP2-associated susceptibility to CBD.  (+info)

IL-4 fails to regulate in vitro beryllium-induced cytokines in berylliosis. (8/92)

Bronchoalveolar lavage (BAL) cells from patients with chronic beryllium disease (CBD) have been used to evaluate the beryllium-specific immune response and potential immunotherapeutics. Beryllium induces interferon-gamma (IFN-gamma), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-10 (IL-10) from BAL cells. An antibody to IL-2 and recombinant human (rHu) IL-10 is able to partially suppress the beryllium-stimulated immune response. To obtain BAL cells, bronchoscopy is required, providing risk to the patient and a limited number of cells to study the immune response. As a result, the objectives of the study were to determine 1) whether CBD peripheral blood mononuclear cells (PBMNs) stimulated with beryllium would produce a similar cytokine pattern as BAL cells, and 2) whether this response could be modulated by interleukin-4 (IL-4), an immunomodulatory cytokine. CBD and normal individuals' PBMN and BAL cells were stimulated with and without beryllium sulfate. To modulate this antigen-stimulated response, we added rHu IL-4 to the unstimulated and beryllium-stimulated cells. IFN-gamma, IL-2, TNF-alpha, IL-6 and IL-10 cytokine concentrations were determined from cell supernatants by enzyme-linked immunosorbent assays (ELISA), while IL-4 messenger ribonucleic acid (mRNA) was assessed using polymerase chain reaction (PCR). Beryllium did not stimulate any of these cytokines from normal PBMNs. Increasing levels of IL-6 and TNF-alpha were produced constituitively by CBD PBMNs over time. Compared to the unstimulated CBD PBMNs, beryllium stimulated significant IFN-gamma, TNF-alpha, IL-2, IL-6 and IL-10 production. This response was similar to that stimulated from CBD BAL cells, although of a much lower magnitude. Low levels of IL-4 mRNA were found in CBD and control PBMNs, which were not increased with beryllium stimulation. The beryllium-stimulated cytokine levels were not decreased by the addition of IL-4. IL-4 was unable to downregulate any of these beryllium-stimulated cytokines from CBD BAL cells or increase IL-4 mRNA from either CBD PBMN or BAL cells, and thus is an unlikely immunomodulatory agent in CBD. From the data, it was concluded that chronic beryllium disease peripheral blood mononuclear cells provide a model to study the beryllium-stimulated immune response. Interleukin-4's inability to downregulate any of the beryllium-stimulated cytokines makes it an unlikely therapeutic candidate in chronic beryllium disease.  (+info)

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