T Cells in Beryllium Sensitization and Disease

描述（由申请人提供）：慢性铍病（Chronic berylium disease， CBD）是一种由工作场所接触铍引起的肉芽肿性肺部疾病，其特征是肺部积聚大量铍特异性CD4+ T细胞。由于其独特的化学和物理性质，铍继续在高科技工业中得到利用。因此，CBD仍然是一个重要的公共卫生问题，有超过100万工人接触过铍并有患病风险。铍致敏是通过血液CD4+ T细胞在培养物中存在铍盐时增殖的能力来检测的。一部分铍致敏（BeS）个体以每年6-8%的速度发展为CBD， CBD的自然史以肺纤维化的发展为特征。从铍致敏到疾病的过程中涉及哪些因素以及各种T细胞亚群如何在这一过程中发挥作用仍然是重要的未解问题，并构成了该应用的基础。我们最近的研究表明，CBD患者血液中铍反应性CD4+ T细胞的频率明显高于BeS患者，并与肺部炎症标志物直接相关，提示循环池中铍特异性T细胞的数量反映了CD4+ T细胞肺泡炎的严重程度。此外，我们的初步数据表明，与BeS受试者相比，CBD患者肺中天然存在的表达foxp3的T调节（Treg）细胞的数量减少。我们假设从铍致敏到CBD的进展是由于肺中存在缺陷和/或功能失调的天然Treg细胞。其直接后果是，致病性铍反应性CD4+ T细胞在血液和肺中积累的数量增加，与过度的T细胞依赖性免疫反应相关。第一个具体目标是分析自然产生的表达foxp3的Treg细胞在疾病进展中的作用。特异性目的2将确定循环铍反应CD4+ T细胞的频率是否作为疾病进展和严重程度的生物标志物，而最终目的将评估抗tnf -a单抗英夫利昔单抗对CBD患者血液和BAL中铍反应CD4+ T细胞和自然发生的调节性CD4+ T细胞的频率和功能的影响。因此，能够检测高风险个体疾病进展的中间生物标志物的开发，以及在治疗开始后监测这些生物标志物的能力，将代表着肉芽肿性肺病以及其他CD4+ T细胞介导的疾病领域的巨大进步。公共卫生相关性：本转化性研究将利用职业性肺病患者的血液和肺标本，开发潜在的生物标志物，预测高风险患者的疾病进展和严重程度。这项研究将进一步加深我们对铍诱导的导致致残性肺功能障碍的免疫机制的理解，可能会改善这类患者的福利。

DESCRIPTION (provided by applicant): 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 its unique chemical and physical properties, beryllium continues to be utilized in high-technology 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 as well as other CD4+ T cell-mediated disorders. 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 high-risk 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.