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IRF7-mediated development of autoreactive B cells and SLE

IRF7 介导的自身反应性 B 细胞和 SLE 的发育

基本信息

批准号：
10888832
负责人：
Ziaur Rahman
金额：
$ 52.88万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-23 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10888832
关键词：
Affect American Antibodies Antigen-Antibody Complex Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving B cell differentiation B-Cell Activation B-Cell Development B-Lymphocytes Biochemical Pathway Bone Marrow Cells Cellular Metabolic Process Clinical Trials Data Deposition Development Diphtheria Toxin Disease Disease Progression Genes Goals Human Immune system Inflammation Interferon Type I Interferons Knowledge Learning LoxP-flanked allele Lupus Nephritis Mediating Metabolic Metabolic Pathway Modeling Morbidity - disease rate Mus Myeloid Cells Nucleic Acids Onset of illness Outcome Pathway interactions Patients Persons Phase Plasma Cells Plasmablast Production Publishing Regulation Risk Role Signal Transduction Structure of germinal center of lymph node Systemic Lupus Erythematosus T cell response T-Lymphocyte Tamoxifen Testing Therapeutic Time Toll-like receptors Toxin Conjugates Up-Regulation Woman autoreactive B cell cell type genome wide association study humoral immunity deficiency improved interferon alpha receptor interferon regulatory factor-7 mortality mouse model pathogenic autoantibodies receptor recurrent infection response risk variant systemic autoimmune disease systemic autoimmunity targeted treatment therapeutic target therapeutically effective tissue injury transcription factor type I interferon receptor

项目摘要

Project Summary Mechanisms that drive the development of autoreactive B cells in an autoimmune disorder systemic lupus erythematosus (SLE) is incompletely understood. Overall goal of the Rahman lab is to delineate the mechanisms that promote the development of autoreactive B cells, autoantibody production and SLE, a debilitating autoimmune disease that affects millions of Americans and people worldwide. Developing a complete understanding of such mechanisms will help develop targeted therapies that would be preferable to currently available SLE treatment options that globally suppress the immune system, and result in recurrent infections and increase disease-associated morbidity and mortality. GWAS studies have identified risk variants in the interferon regulatory factor 7 (IRF7) gene, which increase the risk of developing SLE. IRF7 is the key transcription factor that regulates type I interferon (T1-IFN) response downstream of nucleic acid sensing toll- like receptor (TLR) that promote SLE in mice and humans. Our preliminary data highlight the significance of IRF7 in autoreactive B cell development and SLE manifestations in a well-characterized FcgRIIB-/- SLE model. Published and preliminary data from the FcgRIIB-/- model indicate a critical role for IRF7 and a modest role for T1-IFN signaling in autoimmune responses and SLE development. These data suggest T1-IFN-dependent and -independent roles of IRF7 in autoreactive B cell and SLE development, and point to IRF7 as a potentially better therapeutic target for SLE than T1-IFN blocking therapies alone, although recent clinical trials for T1-IFN receptor blocking therapy showed promising outcome. However, we know little about the cell type-specific role of IRF7 in SLE development, although its role in T1-IFN production by pDCs is well established. Importantly, B cell-intrinsic and -extrinsic roles of IRF7 in autoreactive B cell development via extrafollicular antibody-forming cell (AFC) and follicular germinal center (GC) pathways in SLE are not known. Also, T1-IFN-independent IRF7 role in SLE remains unknown. We hypothesize that IRF7 regulates B cell-intrinsic and -extrinsic, and T1-IFN- dependent and -independent mechanisms in autoreactive B cell development in the AFC and GC pathways, leading to pathogenic autoantibody production and SLE. This hypothesis is supported by our preliminary data showing 1) a significant upregulation of IRF7 in AFCs (plasmablasts/plasma cells), GC B cells and myeloid cells 2) increased IRF7 expression in activated B cells from SLE patients 3) a drastic reduction in autoimmune AFC and GC responses, autoantibodies and immune complex deposition in SLE-prone FcgRIIB-/- mice deficient in IRF7 4) IRF7 involvement in altered B cell metabolic activity in SLE-prone B cells, and published data revealing 5) a role for IRF7 in mouse and human SLE. The current proposal will help determine B cell-intrinsic and -extrinsic roles and mechanisms by which IRF7 promote autoreactive B cell and SLE development, and whether IRF7 could be a better therapeutic option for SLE than T1-IFN or T1-IFN-receptor blocking alone.

项目总结