PATHOGENIC T CELLS IN BERYLLIUM-INDUCED LUNG DISEASE

慢性铍病(Cbd)是一种肉芽肿性疾病 在1%到5%的暴露于铍的人中，通常在 工作场所。肺是主要的受累器官， 非干酪性肉芽肿和CD4+T细胞积聚。 CBD患者的支气管肺泡灌洗液(BAL)显示为CD4+ T细胞被选择性地激活并具有 在培养中对硫酸铍(BeSO4)作出反应而增殖。 我们实验室的研究发现T细胞发生了变化 BAL与CBD血中受体(TCR)基因表达的比较 病人。特别是，5名CBD患者显示出CD4+T细胞 表达Vbeta3的扩增产物。对TCRβ链(TCRB)进行测序 BAL CD4+T细胞表达的α-链(TCRA)连接区 显示出克隆性T细胞扩增。来自不同患者的克隆 被发现表达几乎相同的TCRs。我们假设这些 扩增的CD4+T细胞克隆对铍多肽有反应 患者肺中的复合体，在发病机制中起重要作用 疾病的威胁。 有人提出研究证实这些T细胞克隆是有选择性的 在CBD患者中扩张，因此不存在于 健康对照组或其他肉芽肿性疾病患者。 我们还将研究CBD患者在随后患病时的BAL 这些T细胞克隆持续存在的进展。vbl.使用 对这些患者进行BeSO4斑贴测试，我们将确定 渗入皮肤的CD4+细胞也使用类似的TCR。的TCR 体内克隆扩增也将与BAL表达的TCR进行比较 和体外BeSO4刺激后的外周血T细胞。 单独的研究将集中在铍反应的机制上 CBD患者外周血中的CD4+T细胞识别抗原产生刺激作用。 表达特定T细胞克隆TCR的CD_4~+T细胞杂交瘤 将使用CBD患者的扩张来分析对BeSO4的反应 并确定响应是否受特定自我类别的限制 主要组织相容性复合体(MHC)分子。其他研究 将检查是否需要抗原处理来刺激 这些T细胞杂交瘤。总之，这些研究将提供新的 对CBD和其他肉芽肿免疫发病机制的认识 精神错乱。

Chronic beryllium disease (CBD) is a granulomatous disorder which occurs in one to five percent of individuals exposed to beryllium usually in the workplace. The lung is the predominant organ affected, with noncaseating granulomas and the accumulation of CD4+ T cells. Bronchoalveolar lavage (BAL) fluid from CBD patients demonstrates CD4+ T cells which have been selectively activated and have the ability to proliferate in response to beryllium sulfate (BeSO4) in culture. Studies from our laboratory have found alterations in the T cell receptor (TCR) gene expression in the BAL compared to blood of CBD patients. In particular, five CBD patients demonstrated CD4+ T cell expansions expressing Vbeta3. Sequencing the TCR beta-chain (TCRB) and alpha-chain (TCRA) junctional regions expressed in BAL CD4+ T cells demonstrated clonal T cell expansions. Clones from different patients were found to express nearly identical TCRs. We 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 confirm that these T cell clones are selectively expanded in CBD patients and therefore not present in the lungs of healthy control subjects or patients with other granulomatous disorders. We 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 BeSO4 in these same patients, we will determine whether similar TCRs are used by CD4+ cells infiltrating the skin. The TCR of in vivo clonal expansions will also be compared to TCR expressed by BAL and blood T cells after stimulation with BeSO4 in vitro. Separate studies will focus on the mechanism in which beryllium-reactive CD4+ T cells in CBD patients recognize antigen resulting in stimulation. CD4+ T cell hybridomas expressing the TCR of particular T cell clonal expansions in CBD patients will be used to analyze the response to BeSO4 and determine whether responses are restricted by particular self class II major histocompatibility complex (MHC) molecules. Additional studies will examine whether antigen processing is required for stimulation of these T cell hybridomas. Together, these studies will provide new insight into the immunopathogenesis of CBD and other granulomatous disorders.