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

研究 IgG4 相关疾病的自身免疫卓越中心

基本信息

批准号：
9915860
负责人：
SHIV Subramaniam PILLAI
金额：
$ 44.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915860
关键词：
Affect Antigens Apoptosis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes CD4 Positive T Lymphocytes Cell Death Cell Differentiation process Cells Cicatrix Clonal Expansion Color Cytotoxic T-Lymphocytes Development Diffuse Disease Enzymes Exhibits Fibroblasts Fibrosis Fostering Gene Expression Hematopoietic stem cells IgG4 Image Immune Interleukin-1 Intestines Knowledge Lesion Microbe Molecular Myofibroblast Network-based Organ Pathogenesis Patients Peptide Library Pilot Projects Population Principal Investigator Role Somatic Mutation Systemic Scleroderma T cell differentiation T-Lymphocyte Testing Tissues Yeasts base cytokine cytotoxic disorder subtype gut microbiome macrophage metagenome metatranscriptomics microbial microbiome microorganism antigen neural network programs transcriptomics treatment response wound healing

项目摘要

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.

项目总结