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.
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.
|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|
|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|
|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|
|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|
|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|
|McKee, A S; Mack, D G; Crawford, F et al. (2015) MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4âº T-cell priming. Mucosal Immunol 8:1237-47|
|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|
|Li, L; Huang, Z; Gillespie, M et al. (2014) p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation. Hum Immunol 75:1155-62|
|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|
|Bowerman, Natalie A; Falta, Michael T; Mack, Douglas G et al. (2014) Identification of multiple public TCR repertoires in chronic beryllium disease. J Immunol 192:4571-80|
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