Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease.
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Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4(+) T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP-restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4(+) T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2-mimotope and HLA-DP2-plexin A4 tetramers detected high frequencies of CD4(+) T cells specific for these ligands in all HLADP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4(+) T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD. (+info)
Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.
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The increasing use of beryllium in a variety of industries continues to be a hazard. New cases are still being reported to the UK Beryllium Case Registry, now numbering 60 in the period 1945-1988. The majority of cases follow inhalation which results in acute beryllium disease (chemical pneumonitis) or more commonly chronic beryllium disease--a granulomatous pneumonitis. Granulomatous skin nodules also occur following local implantation. The clinical and radiological features are briefly described with the emphasis on pathology and immunology. Laser microprobe mass spectrometry analysis of tissue sections is a major advance in diagnosis. Detection of beryllium distinguishes the granulomas of chronic beryllium disease from other diseases, in particular sarcoidosis. The role of beryllium lymphocyte transformation tests is discussed. Chronic beryllium disease is steroid dependent and local excision of skin lesions appears to be curative. There is no evidence that beryllium is carcinogenic. (+info)
Role of in vitro and in vivo tests of hypersensitivity in beryllium workers.
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The value of the beryllium macrophage migration inhibition (Be MIF) and Mantoux tests in the diagnosis of chronic beryllium disease and in the detection of hypersensitivity in healthy beryllium workers is demonstrated. In the absence of steroid treatment the Be MIF test is positive in chronic beryllium disease patients. Seven of 50 (14%) helathy beryllium workers were Be MIF positive, while all the control subjects, normal and sarcoidosis patients, were negative. Healthy beryllium workers tend to be more often Mantoux negative than a comparable group of non-exposed workers, and although not conclusive this finding correlates with a positive Be MIF test. Although the detection of hypersensitivity is not diagnostic of disease, the Be MIF test can be used as an additional method for monitoring the health of beryllium workers. The full significance of our results should be assessed by a long-term study. (+info)
Beryllium exposure and pulmonary function: a cross sectional study of beryllium workers.
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A cross sectional study of 297 white male workers employed in a large beryllium plant was conducted to test the hypothesis that long term exposure to beryllium is associated with decrements in pulmonary function. Spirometric measurement of pulmonary function, chest radiographs, and arterial blood gas measurements were collected. After controlling for age, height, and smoking in multivariate regression models, decrements in FVC and FEV1 were found to be associated with cumulative exposure to beryllium in the period up until 20 years before the health survey. These decrements were observed in workers who had no radiographic abnormalities. The alveolar-arterial oxygen difference was associated with cumulative exposure in the 10 years immediately before survey, after controlling for age and smoking. These findings suggest that beryllium may have both short and long term pulmonary effects that are distinct from the classic forms of acute and chronic beryllium disease. (+info)