Adaptive immunity in primary sclerosing cholangitis patients at risk for colorectal cancer

有结直肠癌风险的原发性硬化性胆管炎患者的适应性免疫

基本信息

批准号：
10409786
负责人：
Dustin Shaw
金额：
$ 5.18万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409786
关键词：
Adaptive Immune System Address Antigens Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes CD4 Positive T Lymphocytes CD69 antigen Celiac Disease Cells Clonal Expansion Clonality Clone Cells Colon Colorectal Cancer Crohn&apos s disease Data Development Diagnosis Diagnostic Disease Dysplasia Epithelial Cells Etiology FOXP3 gene Fibrosis Gene Expression Gene Expression Profile Genes Genetic Transcription HLA Antigens HLA-DRB1 Health Human Immune Immunoglobulin G Immunoglobulins Individual Infiltration Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Interleukin-17 Intervention Investigation Lamina Propria Link Liver Fibrosis Liver diseases Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Medical Molecular Nature Outcome Outcome Study Pathogenicity Pathology Patients Plasma Cells Population Populations at Risk Property Publishing Risk Role Signal Transduction Specificity T cell response T-Lymphocyte T-cell receptor repertoire Therapeutic Therapeutic Intervention Time Tissue Sample Tissues Ulcerative Colitis Vulnerable Populations Work adaptive immune response adaptive immunity base bile duct cell type chronic autoimmune disease colorectal cancer prevention colorectal cancer risk comorbidity genome wide association study high risk human tissue insight interdisciplinary approach plasma cell differentiation predictive signature primary sclerosing cholangitis response targeted treatment therapeutic development therapeutic target tool development tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Primary sclerosing cholangitis (PSC) is a class II human leukocyte antigen (HLA-II) associated autoimmune disease of the liver, characterized by the progressive fibrosis of the bile ducts, for which there is no cure. Upwards of 80% of individuals with PSC also have inflammatory bowel disease (IBD), and are at five times greater risk for colorectal cancer (CRC) than individuals with IBD alone. PSC is a major health concern, as 50% of individuals with PSC-IBD develop CRC within 25 years of diagnosis. The mechanisms causing the high risk of CRC in PSC-IBD, however, are unknown. Our group took an unbiased transcriptional approach to analyzing human colonic tissue in order to investigate the mechanisms of the increased risk of CRC and other pathologies in PSC. Our analysis revealed that expression of immunoglobulin G1 (IgG1) and genes downstream of interleukin-17 (IL-17) signaling accurately predicted all cases of dysplasia (the precursor to CRC) in patients with PSC-IBD. Further investigation suggests that these transcriptional signals may originate from an increase in adaptive immune cells, namely IgG plasma cells and IL-17+ CD4 T-cells, in the colon of PSC subjects that develop dysplasia. The objective of this study is to use primary human tissue samples to better understand the relationship between these cell types and the development of dysplasia in PSC-IBD patients. Previous work demonstrates that in HLA-II associated autoimmunity, a pathogenic antigen causes clonal expansion of plasma cells and T-cells which leads to tissue destruction. We hypothesize that in PSC, IgG plasma cells and IL-17+ CD4 T-cells are clonally expanded in response to a pathogenic antigen. Moreover, we hypothesize that these cells induce dysplasia in PSC subjects. To address this hypothesis, we propose to 1) dissect the relationship between plasma cells, T-cells, and dysplasia in PSC-IBD as compared to IBD alone; and 2) further characterize the nature and clonality of these cellular responses, and use this to identify the causative antigen. We will take a multidisciplinary approach, including single cell transcriptional analysis, to complete this investigation. As this study will be done on human tissue, the results will be directly applicable to understanding of the development of CRC in PSC-IBD. Additionally, this work may help identify a causative antigen driving dysplasia in PSC-IBD. Ultimately, this will allow for the development of therapeutics specific for individuals with PSC. This work will also contribute to our understanding of how adaptive immunity can induce cancer.

项目概要/摘要原发性硬化性胆管炎 (PSC) 是 II 类人类白细胞抗原 (HLA-II) 相关的自身免疫性疾病肝脏疾病，其特征是胆管进行性纤维化，目前无法治愈。超过 80% 的 PSC 患者同时患有炎症性肠病 (IBD)，这一比例是其五倍与仅患有 IBD 的个体相比，结直肠癌 (CRC) 的风险更大。 PSC 是一个主要的健康问题，因为 50% 的 PSC-IBD 患者在诊断后 25 年内发展为 CRC。造成高的机制然而，PSC-IBD 中发生 CRC 的风险尚不清楚。我们的小组采取了一种公正的转录方法分析人类结肠组织，以研究结直肠癌和其他疾病风险增加的机制 PSC 中的病理。我们的分析表明，免疫球蛋白 G1 (IgG1) 和基因的表达白细胞介素 17 (IL-17) 信号下游准确预测了所有发育异常病例（发育异常的前兆） PSC-IBD 患者中的 CRC）。进一步的研究表明这些转录信号可能源自来自结肠中适应性免疫细胞（即 IgG 浆细胞和 IL-17+ CD4 T 细胞）的增加发生发育不良的 PSC 受试者。本研究的目的是利用原始人体组织样本更好地了解这些细胞类型与 PSC-IBD 发育异常的发展之间的关系患者。先前的工作表明，在 HLA-II 相关的自身免疫中，致病性抗原会导致浆细胞和 T 细胞的克隆扩增，导致组织破坏。我们假设在 PSC 中， IgG 浆细胞和 IL-17+ CD4 T 细胞响应致病性抗原而克隆扩增。而且，我们假设这些细胞会引起 PSC 受试者的发育不良。为了解决这个假设，我们建议 1) 与单独的 IBD 相比，剖析 PSC-IBD 中浆细胞、T 细胞和发育异常之间的关系； 2）进一步表征这些细胞反应的性质和克隆性，并用它来识别致病抗原。我们将采取多学科方法，包括单细胞转录分析，完成这项调查。由于这项研究将在人体组织上进行，因此结果将直接适用于了解 PSC-IBD 中 CRC 的发展。此外，这项工作可能有助于确定病因 PSC-IBD 中抗原驱动的发育不良。最终，这将有助于开发针对特定疾病的治疗方法患有 PSC 的个体。这项工作也将有助于我们理解适应性免疫如何诱导癌症。