Cytotoxic CD4+ T cells and autoimmune fibrotic disorders

项目总结 这个项目关注的是一种自身免疫性纤维化疾病的潜在基础，IgG4- 相关疾病。我们将使用疾病组织、细胞的多色多光谱成像 距离作图以及单细胞转录转录以询问IgG4组织- 相关疾病。特别是，我们希望鉴定和量化CD4+细胞毒性T细胞 和激活的B细胞亚群，并更好地了解它们是否直接对 组织中的细胞死亡，从而导致纤维化，或者如果它们主要分泌纤维化产物。 我们还想了解CD4+细胞毒性T细胞的分子基础 差异化。我们将测试两个相互竞争但相互非排他性的假设--一个 CD4+T细胞在激活的B细胞的帮助下推动组织细胞死亡，这是 一种是纤维化，另一种是活化的T细胞分泌的细胞因子和酶以及 疾病相关的B细胞是导致纤维化的原因。我们还将检查这些交互 疾病中获得性免疫细胞和先天免疫细胞之间的关系，并识别触发 患者的B和T细胞克隆性扩增。我们还将探讨是否有可能 造血干细胞或CD4+CTL克隆中的体细胞突变有助于 疾病发病机制。

PROJECT SUMMARY This project focuses on the underlying basis of an autoimmune fibrotic disorder, IgG4- related disease. We will use multi-color multispectral imaging of disease tissues, cell distance mapping as well as single-cell transcriptomics to interrogate tissues from IgG4- related disease. In particular we wish to identify and quantitate CD4+cytotoxic T cells and activated B cell subsets and better understand whether they directly contribute to cell death in tissues and thus to fibrosis, or if they primarily secrete fibrogenic products. We also want to understand the molecular basis by which CD4+cytotoxic T cells differentiate. We will test two competing but mutually non-exclusive hypotheses - one that CD4+T cells, with the help of activated B cells drive tissue cell death as a prelude to fibrosis, and the other that the cytokines and enzymes secreted by activated T cells and disease-related B cells are causal for fibrosis. We will also examine the interactions between adaptive and innate immune cells in disease and identify antigens that trigger clonally expanded B and T cells in patients. We will also explore the possibility that somatic mutations in hematopoietic stem cells or in CD4+CTL clones contribute to disease pathogenesis.