An autoimmune center of excellence for the study of IgG4-related disease

项目摘要 该项目的重点是两种自身免疫性纤维化疾病的基础，IgG 4- 相关疾病和系统性硬化症。我们将使用多色多光谱成像， 疾病组织，细胞距离作图以及单细胞转录组学， 询问来自IgG 4相关疾病组织。我们特别希望确定和 定量CD 4+细胞毒性T细胞和活化的B细胞亚群， 它们是否直接导致组织中的细胞死亡并因此导致纤维化，或者它们是否 主要分泌纤维化产物。我们还想了解分子基础， CD 4+细胞毒性T细胞的分化。我们将测试两个相互竞争但互不- 唯一的假设-一个是CD 4 +T细胞，在活化的B细胞的帮助下， 组织细胞死亡作为纤维化的前奏，另一种是细胞因子和酶 由活化的T细胞和疾病相关的B细胞分泌的IL-6是纤维化的原因。我们将 还研究了疾病中适应性和先天免疫细胞之间的相互作用， 鉴定触发患者中克隆扩增的B和T细胞的抗原。我们还将 探讨造血干细胞或CD 4 +CTL中的体细胞突变的可能性， 克隆有助于疾病的发病机理。我们还将检查肠道 微生物基因表达揭示疾病子集之间的差异或解释 对治疗的反应。微生物代谢产物对免疫的可能贡献 细胞分化将被检查，激活宿主T细胞的微生物抗原将 也被识别。

PROJECT SUMMARY This project focuses on the underlying basis of two autoimmune fibrotic disorders, IgG4- related disease and systemic sclerosis. 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. We will also examine whether intestinal microbial gene expression reveals differences between subsets of disease or explains responsiveness to therapy. The possible contribution of microbial metabolites to immune cell differentiation will be examined and microbial antigens that activate host T cells will also be identified.