Pathogenic T Cells in Chronic Beryllium Disease

描述（由申请人提供）：慢性铍病（CBD）以肉芽肿性炎症和肺进行性纤维化为特征。这种疾病是由于在工作场所接触铍而引起的，它仍然是一个主要的公共卫生问题，目前估计有80万接触者处于危险之中。大量证据表明，CD4+ T细胞是CBD发病机制的核心，疾病与靶器官中铍特异性CD4+ T细胞的积累有关。本研究的主要目的是阐明致病性CD4+ T细胞识别CBD中铍的机制。先前对CBD患者肺部CD4+ T细胞的研究显示，产生th1型细胞因子的铍特异性T细胞大量寡克隆扩增。铍特异性T细胞的致病亚群在个体患者和不同患者之间表达相同的相关T细胞受体（tcr）。其他研究表明，向致病性CD4+ T细胞呈递铍依赖于HLA-DP的特定等位基因，而呈递铍的DP等位基因与疾病易感性相关的等位基因相匹配。铍引起的异常强烈的T细胞反应的基础及其与这些发现的关系尚不清楚。目前应用的研究将验证CBD中对铍的剧烈反应与TCR与多个广泛表达的呈现hla - dp肽复合物的铍相互作用有关的假设。第一个特定目标的研究将确定与HLA-DP2结合的肽的序列和基序，并允许抗原特异性tcr识别铍。肽序列和基序将用于鉴定和验证可能介导铍识别的普遍的自肽和蛋白质。在单独的研究中，对不同肽组有反应的肺T细胞将在TCR表达方面进行表征，以了解每个DP2肽/铍复合物是否诱导不同或广泛重叠的应答T细胞亚群。进一步的研究将确定荧光dp2肽/铍多聚体（“四聚体”）是否可用于识别和表征CBD患者肺部和外周血中的铍反应性T细胞。研究的最终目的将确定为什么只有某些HLA-DP等位基因似乎能够呈现铍，以及是否呈现仅限于DP。总之，这些研究将为CBD的免疫发病机制提供新的见解，并为其他CD4 + T细胞介导的疾病提供重要信息。

DESCRIPTION (provided by applicant): Chronic beryllium disease (CBD) is characterized by granulomatous inflammation and progressive fibrosis in the lung. The disease is caused by exposure to beryllium in the workplace, and it continues to be a major public health concern with an estimated 800,000 exposed individuals currently at risk. Considerable evidence indicates that CD4+ T cells are central to the pathogenesis of CBD and that disease is associated with the accumulation of beryllium-specific CD4+ T cells in the target organ. The major goal of the studies in this application is to elucidate the mechanism by which pathogenic CD4+ T cells recognize beryllium in CBD. Previous studies of CD4+ T cells in the lungs of CBD patients have shown large oligoclonal expansions of beryllium-specific T cells that produce Th1-type cytokines. Pathogenic subsets of beryllium-specific T cells in individual patients and among different patients were noted to express the same related T cell receptors (TCRs). Other studies have demonstrated that presentation of beryllium to pathogenic CD4+ T cells is dependent on particular alleles of HLA-DP, and the DP alleles that present beryllium match those implicated in disease susceptibility. The basis for the unusually strong T cell response elicited by beryllium and how it relates to these findings is unclear. Studies in the current application will test the hypothesis that the dramatic response to beryllium in CBD relates to TCR interactions with multiple widely expressed sets of beryllium presenting HLA-DP-peptide complexes. Studies in the first specific aim will define the sequence and motif of peptides that bind to HLA-DP2 and that allow recognition of beryllium by antigen-specific TCRs. The peptide sequences and motifs will be used to identify and verify prevalent self-peptides and proteins that are likely to mediate recognition of beryllium. In separate studies, lung T cells that respond to the different peptide sets will be characterized in regard to TCR expression to understand whether each DP2- peptide/beryllium complex induces distinct or broadly overlapping subsets of responding T cells. Additional studies will determine whether fluorescent DP2-peptide/beryllium multimers ("tetramers") can be used to identify and characterize beryllium-reactive T cells in the lungs and peripheral blood of patients with CBD. Studies in the final aim will determine why only certain HLA-DP alleles seem to be capable of presenting beryllium and whether presentation is limited to DP. Together, these studies will provide new insight into the immunopathogenesis of CBD as well as important information for other CD4 + T cell mediated diseases.