PATHOGENIC T CELLS IN CHRONIC BERYLLIUM DISEASE

描述(改编自调查人员摘要)：慢性铍 疾病(CBD)是一种在个体中发展起来的肉芽肿性疾病 以前接触过铍，通常是在工作场所。肺气是 受累的主要器官和肉芽肿性炎症是 与组织和组织中CD4T细胞的聚集有关 支气管肺泡灌洗(BAL)。来自调查人员的研究 实验室发现T细胞受体(TCR)表达发生变化 在CBD患者的BAL中包括扩增的CD4T细胞群 表达特定的TCR Vbeta区。TCRβ链的测序 在BAL中表达的(TCRB)和TCRα链(TCRA)连接区 CD4T细胞表现出克隆性T细胞扩张，来自 不同的CBD患者表达的TCR几乎相同。这个 研究人员现在假设这些扩增的CD4T细胞克隆是 对患者肺内铍/多肽复合体的反应 在疾病的发病机制中起着重要作用。建议进行研究以 证实这些T细胞克隆在CBD患者中得到选择性扩增 因此，在健康对照组和健康人的肺中不存在 其他肺肉芽肿性疾病患者。他们还将学习 CBD患者在疾病进展的后续时间的BAL 这些T细胞克隆的持续存在。对BeS04进行补丁测试 在这些患者中，研究将检查类似的TCR是否 由渗入皮肤的CD4T细胞使用。体内TCR的研究进展 克隆扩张也将与BAL和BAL表达的TCR进行比较 CBD患者的血液T细胞识别抗原并被刺激。 表达特定克隆性TCR的CD4T细胞杂交瘤 将使用CBD患者的扩张来分析对BeS04的反应 并确定回答是否受到自我II类专业的限制 组织相容性复合体(MHC)抗原。更多的研究将 检查是否需要抗原处理以进行刺激和 将表征铍/多肽/MHC络合物的性质 参与刺激铍反应性T细胞。

DESCRIPTION (Adapted from Investigator's abstract): Chronic beryllium disease (CBD) is a granulomatous disorder that develops in individuals previously exposed to beryllium usually in the workplace. The lung is the predominant organ involved and granulomatous inflammation is associated with the accumulation of CD4+ T-cells in tissue and broncholveolar lavage (BAL). Studies from the investigators laboratories have found alterations in T-cell receptor (TCR) expression in the BAL of CBD patients including expanded CD4+ T-cell populations that express particular TCR Vbeta regions. Sequencing TCR beta-chain (TCRB) and TCR alpha-chain (TCRA) junctional regions expressed in BAL CD4+ T-cells demonstrated clonal T-cell expansions, and clones from different CBD patients were found to express nearly identical TCRs. The investigators now hypothesize that these expanded CD4+ T-cell clones are responding to beryllium/peptide complexes in the lungs of patients and are important in the pathogenesis of disease. Studies are proposed to verify that these T-cell clones are selectively expanded in CBD patients and, therefore, are not present in the lungs of healthy controls and patients with other granulomatous lung disorders. They will also study BAL in CBD patients at subsequent times of disease progression for the continued presence of these T-cell clones. Using patch testing to BeS04 in these same patients, studies will examine whether similar TCR are used by CD4+ T-cells infiltrating into the skin. The TCR of in vivo clonal expansions will also be compared to TCR expressed by BAL and blood T-cells in CBD patients recognize antigen and are stimulated. CD4+ T-cell hybridomas expressing the TCR of particular clonal expansions in CBD patients will be used to analyze the response to BeS04 and determine whether responses are restricted by self class II major histocompatibility complex (MHC) antigens. Additional studies will examine whether antigenic processing is required for stimulation and will characterize the nature of the beryllium/peptide/MHC complex involved in stimulating beryllium-reactive T-cells.