Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of large numbers of beryllium-specific CD4* T cells in the lung. Due to unique chemical and physical properties, beryllium continues to be utilized in hightechnology industries. Thus, CBD remains an important public health concern with more than 1,000,000 workers having been exposed to beryllium and at risk for disease development. Beryllium sensitization is detected by the ability of blood CD4* T cells to proliferate in the presence of beryllium salts in culture. A subset of beryllium-sensitized (BeS) individuals progress to CBD at a rate of 6-8% per year, and the natural history of CBD is characterized by the development of lung fibrosis. What factors are involved in the progression from beryllium sensitization to disease and how various T cell subsets play a role in this progression remain important unanswered questions and form the basis of this application. We have recently shown that the frequency of beryllium-responsive CD4^ T cells in blood of CBD patients is significantly greater than that found in BeS subjects and directly correlates with markers of lung inflammation, suggesting that the number of beryllium-specific T cells in the circulating pool reflects the severity of the CD4* T cell alveolitis. In addition, our preliminary data suggest that the quantity of naturally-occurring, Foxp3-expressing T regulatory (Treg) cells in the lung of CBD patients is diminished compared to the lung of BeS subjects. We hypothesize that progression from beryllium sensitization to CBD is due to the presence of deficient and/or dysfunctional naturally-occurring Treg cells in lung. As a direct consequence, an increased number of pathogenic beryllium-responsive CD4^ T cells accumulate in blood and lung, associated with an exaggerated T cell dependent immune response. The first specific aim will analyze the role of naturally-occurring, Foxp3-expressing Treg cells in disease progression.
Specific aim 2 will determine whether the frequency of circulating beryllium-responsive CD4'' T cells serves as a biomarker of disease progression and severity while the final aim will evaluate the effects of the anti-TNF-a mAb, infliximab, on the frequency and function of beryllium-responsive CD4* T cells and naturally-occurring regulatory CD4* T cells in blood and BAL of CBD patients. Thus, the development of intermediate biomarkers capable of detecting disease progression in high-risk individuals and the ability of monitor these biomarkers after treatment initiation would represent a tremendous advance in the field of granulomatous lung disease.

Public Health Relevance

This translational study will utilize blood and lung specimens from human subjects with an occupational lung disorder for the development of potential biomarkers that predict disease progression and severity in highrisk subjects. This study will further our understanding of the beryllium-induced immune mechanisms that lead to disabling lung dysfunction, potentially leading to an improved welfare of this patient population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES011810-07
Application #
8185139
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
7
Fiscal Year
2010
Total Cost
$309,184
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Mroz, Margaret M; Ferguson, John H; Faino, Anna V et al. (2018) Effect of inhaled corticosteroids on lung function in chronic beryllium disease. Respir Med 138S:S14-S19
Li, Li; Silveira, Lori J; Hamzeh, Nabeel et al. (2016) Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis. Eur Respir J 47:1797-808
Falta, M T; Tinega, A N; Mack, D G et al. (2016) Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice. Mucosal Immunol 9:218-28
Tooker, Brian C; Ozawa, Katherine; Newman, Lee S (2016) CpG promoter methylation status is not a prognostic indicator of gene expression in beryllium challenge. J Immunotoxicol 13:417-27
Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7
McKee, A S; Mack, D G; Crawford, F et al. (2015) MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4? T-cell priming. Mucosal Immunol 8:1237-47
Tooker, Brian C; Brindley, Stephen M; Chiarappa-Zucca, Marina L et al. (2015) Accelerator mass spectrometry detection of beryllium ions in the antigen processing and presentation pathway. J Immunotoxicol 12:181-7
Li, Li; Hamzeh, Nabeel; Gillespie, May et al. (2015) Beryllium increases the CD14(dim)CD16+ subset in the lung of chronic beryllium disease. PLoS One 10:e0117276
Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42
Mack, Douglas G; Falta, Michael T; McKee, Amy S et al. (2014) Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc Natl Acad Sci U S A 111:8553-8

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