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

• 批准号: 8680709
• 负责人: SHIV Subramaniam PILLAI
• 金额: $ 71.29万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680709
• 关键词: Antibodies; Antibody Repertoire; Antigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cell Surface Proteins; Cells; Cessation of life; Characteristics; Cicatrix; Clinical; Clonal Expansion; Clone Cells; Color; Cytometry; Development; Disease; Epigenetic Process; Expression Library; Fc Receptor; Fibrosis; Flow Cytometry; Gene Expression; Gene Expression Profiling; Genetic Predisposition to Disease; Genotype; Hamman-Rich syndrome; Human; IgG4; Immunology; Inflammatory; Knowledge; Lesion; Libraries; Light; MHC Class II Genes; Molecular; Organ; Pathogenesis; Pathway interactions; Patients; Peptides; Phlebitis; Pilot Projects; Plasma; Plasmablast; Property; Proteins; Quality of life; Reagent; Recombinant Proteins; Research Design; Role; Serum; Source; Steroids; Surface; Survivors; Swelling; Syndrome; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; base; commensal microbes; exome sequencing; glycosylation; human monoclonal antibodies; interdisciplinary approach; liquid chromatography mass spectrometry; microbial community; multidisciplinary; novel; oral tissue; premature; protein expression; protein metabolite; response; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): In this project we will seek to better understand the pathogenesis of lgG4 related disease utilizing a multidisciplinary approach. Based on this knowledge we seek to influence the development of new therapies that may be applicable not just to this disease but to other autoimmune and fibrotic diseases as well. lgG4 related disease is a multisystem disorder characterized by tissue swelling/s, storiform fibrosis, obliterative phlebitis and high levels of plasma lgG4. While this disorder is likely to be autoimmune, an aberrant response to a pathogenic or commensal microbe has not been ruled out. In the principal proposal we will study in depth activated effector CD4+ T cell clones in subjects with lgG4-Related disease. We will examine the T cell receptor repertoire by Next Gen Sequencing, and obtain a detailed analysis of gene and protein expression in these clones in order to better understand how they are generated and how they function. We will perform single cell RNA seq and mass cytometry to understand the clonal origins of these effector T cells. Unique cell surface proteins found only in disease subjects will be identified. The mechanism by which these T cell clones influence fibrosis will be examined. The antibody repertoire of plasmablasts will also be identified, and novel disease related human monoclonal antibodies will be generated and the properties of clonally expanded plasmablasts will also be studied. Human ORFeome libraries will be interrogated with serum and disease related monoclonal lgG4 antibodies and disease specific antigens will be identified and used as tools to identify the antigenic peptides recognized by clonally expanded CD4+ T cells. In the Collaborative project studies will be performed to correlate oral, tissue and gut microbial communities with genetic susceptibility markers and subsets of patients with distinct functional characteristics of the clonal effector T cells in disease subjects. In the Pilot Project the glycosylation of lgG4, in subjects with active disease will be analyzed and its ability to influenc binding to different human Fc receptors will be examined. RELEVANCE: The proposed multidisciplinary studies are designed not only to benefit patients with lgG4-related disease, but to also benefit a host of other disorders including many other autoimmune diseases and other diseases including idiopathic pulmonary fibrosis. Principal Project: Studies on the Immunology of IgG4-related diseases Project Leader (PL): Shiv S. Pillai DESCRIPTION (as provided by applicant): lgG4-Related Disease is a multi-system disorder encompassing a host of previously described syndromes, all now recognized to be characterized by tumescent lesions, storiform fibrosis, obliterative phlebitis and large amounts of serum lgG4. Clinical improvement is seen with steroids in many subjects and B cell depletion is also clinically effective. Very little is known about the pathogenesis of this disorder or about th molecular and cellular basis for fibrosis in a host of apparently unrelated disorders. Studies will be performed to define T cell clonal expansions observed by Next Gen Sequencing approaches in subjects with this disease but with distinct organ involvements. Novel surface markers expressed only on effector T cell clones will be investigated as potential targets for therapy. Detailed interrogation of gene expression protein expression and metabolites will be performed by global as well as single cell RNAseq, multi-color flow cytometry, by Cytof mass cytometry, and liquid chromatography-mass spectrometry on clonally expanded T cells and will be conducted in order to understand pathways of potential therapeutic significance that contributes to the development of these T cells as well as to their effector functions in this fibrotic inflammatory disease. A possible role for lgG4 antibodies in this disordr will also be examined. Next Gen Sequencing as well as single cell cloning and sequencing strategies will be used to define plasmablast expansions and to establish specific antibody heavy-light chain pairs that may contribute to the disease. Reagents will be thus generated to identify specific antigens using human ORFeome expression libraries as source of antigen. Determining the B cell specific protein antigen and the use of recombinant proteins will be used to assist the identification of T cell specific peptides. Studies will also be performed on genetic susceptibility to lgG4-RD using Fluidigm based MHC class II genotyping and if indicated from the Immunochip analyses by Exome sequencing. Global comparisons of gene and protein expression will inform the need for epigenetic profiling studies. RELEVANCE: Autoimmune and inflammatory diseases that cause severe tissue scarring or fibrosis can cause premature death and seriously impair the quality of life for survivors. The proposed studies may help not only patients with lgG4-related disease, but also a host of other disorders including many other autoimmune diseases and other diseases including idiopathic pulmonary fibrosis.

描述（由申请人提供）：在本项目中，我们将利用多学科方法更好地了解lgG4相关疾病的发病机制。基于这些知识，我们寻求影响新疗法的发展，这些新疗法可能不仅适用于这种疾病，也适用于其他自身免疫性和纤维化疾病。lgG4相关疾病是一种以组织肿胀、故事状纤维化、闭塞性静脉炎和血浆lgG4高水平为特征的多系统疾病。虽然这种疾病很可能是自身免疫性的，但不排除对病原或共生微生物的异常反应。在主要提案中，我们将深入研究lgg4相关疾病受试者的活化效应CD4+ T细胞克隆。我们将通过Next Gen Sequencing检查T细胞受体库，并获得这些克隆中基因和蛋白质表达的详细分析，以便更好地了解它们是如何产生的以及它们是如何起作用的。我们将进行单细胞RNA测序和大量细胞术来了解这些克隆起源