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

项目总结 这个项目主要关注两种自身免疫性纤维化疾病的潜在基础，IgG4- 相关疾病和系统性硬化症。我们将使用多色多光谱成像技术 疾病组织、细胞距离图以及单细胞转录组学 询问IgG4相关疾病的组织。特别是，我们希望确定和 量化CD4+细胞毒性T细胞和活化的B细胞亚群并更好地了解 它们是否直接导致组织中的细胞死亡从而导致纤维化，或者如果它们 主要分泌致纤维化的产物。我们还想通过以下方式了解分子基础 哪些CD4+细胞毒性T细胞分化。我们将测试两个相互竞争但相互非的 排他性假设--CD4+T细胞在激活的B细胞的帮助下驱动 组织细胞死亡是纤维化的前奏，另一种是细胞因子和酶 由活化的T细胞和疾病相关的B细胞分泌的物质是导致纤维化的原因。我们会 也检查适应性免疫细胞和先天免疫细胞之间的相互作用 识别在患者体内触发克隆扩增的B和T细胞的抗原。我们还将 探索造血干细胞或CD4+CTL的体细胞突变的可能性 克隆在疾病发病机制中起着重要作用。我们还将检查肠道是否 微生物基因表达揭示了疾病亚组之间的差异，或解释了 对治疗的反应性。微生物代谢产物对免疫的可能贡献 将检查细胞分化，激活宿主T细胞的微生物抗原将 也可以确认身份。

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.