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Journal of Immunology (Baltimore, Md. :... Oct 2018Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and...
Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and initiate metal-specific CD4 T cell responses. Chronic beryllium disease (CBD), a life-threatening metal-induced hypersensitivity, is driven by beryllium-specific CD4 Th1 cells that expand in the lung-draining lymph nodes (LDLNs) after beryllium exposure (sensitization phase) and are recruited back to the lung, where they orchestrate granulomatous lung disease (elicitation phase). To understand more about how beryllium exposures impact DC function during sensitization, we examined the early events in the lung and LDLNs after pulmonary exposure to different physiochemical forms of beryllium. Exposure to soluble or crystalline forms of beryllium induced alveolar macrophage death/release of IL-1α and DNA, enhanced migration of CD80 DCs to the LDLNs, and sensitized HLA-DP2 transgenic mice after single low-dose exposures, whereas exposures to insoluble particulate forms beryllium did not. IL-1α and DNA released by alveolar macrophages upregulated CD80 on immature BMDC via IL-1R1 and TLR9, respectively. Intrapulmonary exposure of mice to IL-1R and TLR9 agonists without beryllium was sufficient to drive accumulation of CD80 DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80 DCs in the LDLNs of beryllium-exposed mice. Thus, in contrast to particulate forms of beryllium, which are poor sensitizers, soluble or crystalline forms of beryllium promote death of alveolar macrophages and their release of IL-1α and DNA, which act as damage-associated molecular pattern molecules to enhance DC function during beryllium sensitization.
Topics: Allergens; Animals; Berylliosis; Beryllium; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Movement; Cells, Cultured; Chronic Disease; Dendritic Cells; Enzyme-Linked Immunospot Assay; Humans; Hypersensitivity; Immunization; Lung; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Receptors, Interleukin-1 Type I; Toll-Like Receptor 9
PubMed: 30185516
DOI: 10.4049/jimmunol.1800303 -
American Journal of Respiratory Cell... Jan 2019Epigenetic marks are likely to explain variability of response to antigen in granulomatous lung disease. The objective of this study was to identify DNA methylation and...
Epigenetic marks are likely to explain variability of response to antigen in granulomatous lung disease. The objective of this study was to identify DNA methylation and gene expression changes associated with chronic beryllium disease (CBD) and sarcoidosis in lung cells obtained by BAL. BAL cells from CBD (n = 8), beryllium-sensitized (n = 8), sarcoidosis (n = 8), and additional progressive sarcoidosis (n = 9) and remitting (n = 15) sarcoidosis were profiled on the Illumina 450k methylation and Affymetrix/Agilent gene expression microarrays. Statistical analyses were performed to identify DNA methylation and gene expression changes associated with CBD, sarcoidosis, and disease progression in sarcoidosis. DNA methylation array findings were validated by pyrosequencing. We identified 52,860 significant (P < 0.005 and q < 0.05) CpGs associated with CBD; 2,726 CpGs near 1,944 unique genes have greater than 25% methylation change. A total of 69% of differentially methylated genes are significantly (q < 0.05) differentially expressed in CBD, with many canonical inverse relationships of methylation and expression in genes critical to T-helper cell type 1 differentiation, chemokines and their receptors, and other genes involved in immunity. Testing of these CBD-associated CpGs in sarcoidosis reveals that methylation changes only approach significance, but are methylated in the same direction, suggesting similarities between the two diseases with more heterogeneity in sarcoidosis that limits power with the current sample size. Analysis of progressive versus remitting sarcoidosis identified 15,215 CpGs (P < 0.005 and q < 0.05), but only 801 of them have greater than 5% methylation change, demonstrating that DNA methylation marks of disease progression changes are more subtle. Our study highlights the significance of epigenetic marks in lung immune response in granulomatous lung disease.
Topics: Berylliosis; Biomarkers; Case-Control Studies; Chronic Disease; DNA Methylation; Female; Gene Expression Profiling; Gene Expression Regulation; Genome, Human; Humans; Male; Middle Aged; Sarcoidosis, Pulmonary
PubMed: 30141971
DOI: 10.1165/rcmb.2018-0177OC -
Annals of the American Thoracic Society Apr 2018Metal-induced hypersensitivity is driven by T-cell sensitization to metal ions. Although numerous metals are associated with the development of diffuse parenchymal lung... (Review)
Review
Metal-induced hypersensitivity is driven by T-cell sensitization to metal ions. Although numerous metals are associated with the development of diffuse parenchymal lung disease, beryllium-induced hypersensitivity is the best-studied to date. This review focuses on the interaction between innate and adaptive immunity that leads to the development of chronic beryllium disease. After beryllium exposure, activation of the innate immune system occurs through the engagement of pattern-recognition receptors. This activation leads to cell death, release of alarmins, and activation and migration of dendritic cells to lung-draining lymph nodes. These events culminate in the development of an adaptive immune response that is characterized by beryllium-specific, T-helper type 1-polarized, CD4 T-cells and granuloma formation in the lung. The unique ability of beryllium to bind to human leukocyte antigen-DP molecules that express a glutamic acid at position 69 of the β-chain alters the charge and conformation of the human leukocyte antigen-DP-peptide complex. These changes induce post-translational modifications that are recognized as non-self. In essence, the ability of beryllium to create neoantigens underlies the genesis of chronic beryllium disease, and demonstrates the similarity between beryllium-induced hypersensitivity and autoimmunity.
Topics: Adaptive Immunity; Autoimmunity; Berylliosis; Beryllium; CD4-Positive T-Lymphocytes; Genetic Predisposition to Disease; HLA-DP beta-Chains; Humans; Hypersensitivity; Lung
PubMed: 29676647
DOI: 10.1513/AnnalsATS.201707-573MG -
American Journal of Industrial Medicine Jul 2018The beryllium lymphocyte proliferation test (BeLPT), has become the principal clinical test for detecting beryllium sensitization and chronic beryllium disease....
BACKGROUND
The beryllium lymphocyte proliferation test (BeLPT), has become the principal clinical test for detecting beryllium sensitization and chronic beryllium disease. Uninterpretable BeLPT results can occur in a small but significant proportion of tests from poor lymphocyte growth (PG) or over proliferation of lymphocytes (OP). The clinical and laboratory causes of uninterpretable results are not known.
METHODS
BeLPT data from the US Department of Energy-supported Former Worker Screening Program were analyzed for a 10-year period. Drivers of uninterpretable BeLPTs were investigated using multivariable models and classification techniques.
RESULTS
Three participant attributes were significantly associated with PG, while OP showed no significant associations. Serum lot for the lymphocyte growth medium accounted for 21% of the variation in PG and 16% in OP.
CONCLUSION
Serum lots influence the likelihood of having uninterpretable BeLPT. To better understand uninterpretable results and possibly reduce their occurrence, additional laboratory-related factors should be addressed.
Topics: Aged; Berylliosis; Beryllium; Case-Control Studies; Cell Proliferation; Clinical Laboratory Techniques; Female; Humans; Linear Models; Lymphocytes; Male; Mass Screening; Middle Aged; Multivariate Analysis; Occupational Exposure; United States
PubMed: 29574954
DOI: 10.1002/ajim.22842 -
Respiratory Medicine May 2018The clinical effects of inhaled corticosteroids (ICS) on chronic beryllium disease (CBD) are unknown. Although frequently used for symptoms or disease not requiring...
BACKGROUND
The clinical effects of inhaled corticosteroids (ICS) on chronic beryllium disease (CBD) are unknown. Although frequently used for symptoms or disease not requiring systemic therapy, the clinical course of patients on ICS has not been evaluated.
METHODS
In a retrospective cohort study, forty-eight subjects with CBD, diagnosed by granulomas on lung biopsy and treated with inhaled corticosteroids, were matched to sixty-eight subjects with CBD who were not treated. Pulmonary function testing, exercise tolerance, blood BeLPT, BAL cell count, and symptoms were evaluated.
RESULTS
Treated patients showed no significant change over time in pulmonary function, when compared to controls, by forced vital capacity (FVC, p = 0.28) or diffusion capacity (DLCO, p = 0.45) or in exercise tolerance testing. However, symptoms of cough significantly improved in 58% (compared to 17% in controls) and dyspnea improved in 26% after ICS treatment (compared to 0 in controls). Symptoms of cough were improved in patients with a lower baseline FEV1 and FEV1/FVC ratio. Subgroup analysis showed significant lung function response in cases with lower baseline FEV1/FVC and higher residual volume (RV).
CONCLUSION
Although FVC and DLCO did not improve in the ICS treated group, we saw no difference in decline compared to matched controls. Symptoms of dyspnea and cough improved with ICS especially in those with obstruction and air trapping suggesting that these should be considered an indication of ICS use in CBD patients.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Berylliosis; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cohort Studies; Cough; Dyspnea; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Diffusing Capacity; Residual Volume; Retrospective Studies; Vital Capacity
PubMed: 29453139
DOI: 10.1016/j.rmed.2018.01.009 -
BMJ Case Reports Jan 2018Hypercalcaemia occurs in many granulomatous diseases. Among them, sarcoidosis and tuberculosis are the most common causes. Other causes include berylliosis,...
Hypercalcaemia occurs in many granulomatous diseases. Among them, sarcoidosis and tuberculosis are the most common causes. Other causes include berylliosis, coccidioidomycosis, histoplasmosis, Crohn's disease, silicone-induced granulomas, cat-scratch disease, Wegener's granulomatosis and pneumonia. Hypercalcaemia in granulomatous disease occurs as a consequence of dysregulated production of 1,25-(OH)2 D3 (calcitriol) by activated macrophages in granulomas. Hypercalcaemia in patients with infection has been reported in 0%-28% of cases. Uncultured bronchoalveolar lavage cells from patients with produce greater amounts of calcitriol compared with controls. Although Nayar described hypercalcaemia in a case of sepsis associated with intravesical Bacille Calmette Guerin therapy, there are no published reports describing hypercalcaemia in patients with pulmonary infection. We describe a patient with cavitary pulmonary infection with sustained hypercalcaemia that fluctuated and recurred repeatedly over the course of therapy, ultimately culminating in normalisation of serum calcium when therapy had led to cure. Treatment consisted of antituberculous therapy, oral corticosteroids and intravenous bisphosphonates with a favourable outcome.
Topics: Antitubercular Agents; Calcitriol; Humans; Hypercalcemia; Male; Middle Aged; Mycobacterium bovis; Recurrence; Tuberculosis, Pulmonary
PubMed: 29374638
DOI: 10.1136/bcr-2017-222351 -
European Respiratory Review : An... Sep 2017Granulomatous lung diseases are a heterogeneous group of disorders that have a wide spectrum of pathologies with variable clinical manifestations and outcomes. Precise... (Review)
Review
Differential diagnosis of granulomatous lung disease: clues and pitfalls: Number 4 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.
Granulomatous lung diseases are a heterogeneous group of disorders that have a wide spectrum of pathologies with variable clinical manifestations and outcomes. Precise clinical evaluation, laboratory testing, pulmonary function testing, radiological imaging including high-resolution computed tomography and often histopathological assessment contribute to make a confident diagnosis of granulomatous lung diseases. Differential diagnosis is challenging, and includes both infectious (mycobacteria and fungi) and noninfectious lung diseases (sarcoidosis, necrotising sarcoid granulomatosis, hypersensitivity pneumonitis, hot tub lung, berylliosis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, rheumatoid nodules, talc granulomatosis, Langerhans cell histiocytosis and bronchocentric granulomatosis). Bronchoalveolar lavage, endobronchial ultrasound-guided transbronchial needle aspiration, transbronchial cryobiopsy, positron emission tomography and genetic evaluation are potential candidates to improve the diagnostic accuracy for granulomatous lung diseases. As granuloma alone is a nonspecific histopathological finding, the multidisciplinary approach is important for a confident diagnosis.
Topics: Biopsy; Granuloma, Respiratory Tract; Humans; Lung; Lung Diseases; Predictive Value of Tests; Risk Factors
PubMed: 28794143
DOI: 10.1183/16000617.0012-2017 -
Federal Register Jan 2017The Occupational Safety and Health Administration (OSHA) is amending its existing standards for occupational exposure to beryllium and beryllium compounds. OSHA has...
The Occupational Safety and Health Administration (OSHA) is amending its existing standards for occupational exposure to beryllium and beryllium compounds. OSHA has determined that employees exposed to beryllium at the previous permissible exposure limits face a significant risk of material impairment to their health. The evidence in the record for this rulemaking indicates that workers exposed to beryllium are at increased risk of developing chronic beryllium disease and lung cancer. This final rule establishes new permissible exposure limits of 0.2 micrograms of beryllium per cubic meter of air (0.2 [mu]g/m\3\) as an 8-hour time-weighted average and 2.0 [mu]g/m\3\ as a short-term exposure limit determined over a sampling period of 15 minutes. It also includes other provisions to protect employees, such as requirements for exposure assessment, methods for controlling exposure, respiratory protection, personal protective clothing and equipment, housekeeping, medical surveillance, hazard communication, and recordkeeping. OSHA is issuing three separate standards--for general industry, for shipyards, and for construction--in order to tailor requirements to the circumstances found in these sectors.
Topics: Berylliosis; Beryllium; Humans; Occupational Exposure; Occupational Health; Protective Clothing; Respiratory Protective Devices; United States; United States Occupational Safety and Health Administration
PubMed: 28071878
DOI: No ID Found -
Cancer Medicine Dec 2016We aimed at investigating mortality among beryllium-exposed workers, according to solubility of beryllium and beryllium compounds. We conducted an historical cohort...
We aimed at investigating mortality among beryllium-exposed workers, according to solubility of beryllium and beryllium compounds. We conducted an historical cohort study of 16,115 workers employed during 1925-2008 in 15 facilities, including eight entailing exposure to insoluble beryllium and seven entailing exposure to soluble/mixed beryllium compounds, who were followed up for mortality until 2011. Data were analyzed using indirect standardization and Cox regression modeling. Lung cancer standardized mortality ratio (SMR, national reference rates) was 1.02 (95% confidence interval [CI]: 0.94-1.10) in the whole cohort, 0.88 (95% CI: 0.75-1.03) in the insoluble beryllium subcohort, and 1.09 (95% CI: 0.99-1.09) in the soluble/mixed beryllium subcohort. For lung cancer, there was an association with period of hire in soluble/mixed beryllium plants but not in insoluble plants, and, conversely, employment in soluble/mixed plants was associated with increased mortality only among workers hired before 1955. There was no trend with duration of employment. Mortality from chronic beryllium disease increased, in particular, among workers hired before 1955 in soluble/mixed beryllium facilities. There was no increase in lung cancer mortality in the entire cohort and lung cancer mortality was not increased among beryllium workers hired in 1955 or later in soluble/mixed beryllium facilities, or at any time among those employed in insoluble beryllium facilities.
Topics: Berylliosis; Beryllium; Cause of Death; Humans; Male; Mortality; Occupational Exposure; Proportional Hazards Models; Public Health Surveillance; Risk Factors; Time Factors
PubMed: 27766788
DOI: 10.1002/cam4.918 -
Journal of Occupational and... Sep 2016Beryllium workers may better understand their genetic susceptibility to chronic beryllium disease (CBD) expressed as population-based prevalence, rather than odds ratios...
OBJECTIVE
Beryllium workers may better understand their genetic susceptibility to chronic beryllium disease (CBD) expressed as population-based prevalence, rather than odds ratios from case-control studies.
METHODS
We calculated CBD prevalences from allele-specific DNA sequences of 853 workers for Human Leukocyte Antigen (HLA)-DPB1 genotypes and groups characterized by number of E69-containing alleles and by calculated surface electronegativity of HLA-DPB1.
RESULTS
Of 18 groups of at least 10 workers with specific genotypes, CBD prevalence was highest, 72.7%, for the HLA-DPB102:01:02/DPB117:01 genotype. Population-based grouped genotypes with two E69 alleles wherein one allele had -9 surface charge had a beryllium sensitization (BeS) of 52.6% and a CBD prevalence of 42.1%.
CONCLUSIONS
The high CBD and BeS prevalences associated with -9-charged E69 alleles and two E69s suggest that workers may benefit from knowing their genetic susceptibility in deciding whether to avoid future beryllium exposure.
Topics: Berylliosis; Beryllium; Chronic Disease; Genotype; HLA-DP beta-Chains; Humans
PubMed: 27414009
DOI: 10.1097/JOM.0000000000000805