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.

项目摘要驱动自身免疫性症中自动反应性B细胞开发的机制全身性狼疮红斑（SLE）未完全理解。拉赫曼实验室的总体目标是描述促进自动反应性B细胞，自身抗体产生和SLE的机制，A 衰弱的自身免疫性疾病会影响全球数百万美国人和人。开发完全了解这种机制将有助于开发有针对性的疗法当前可用的SLE治疗选项，可在全球抑制免疫系统，并导致经常性感染并增加疾病相关的发病率和死亡率。 GWAS研究已经确定了风险变体在干扰素调节因子7（IRF7）基因中，增加了SLE的风险。 IRF7是关键调节I型干扰素（T1-IFN）核酸感应Toll-下游反应的转录因子像在小鼠和人类中促进SLE的受体（TLR）一样。我们的初步数据突出了自动反应性B细胞开发和SLE表现的IRF7在良好的FCGRIIB - / - SLE模型中。来自FCGRIIB - / - 模型的发布和初步数据表明IRF7的关键作用，以及适度的作用自身免疫反应和SLE发育中的T1-IFN信号传导。这些数据表明T1-IFN依赖性，并且 - IRF7在自动反应性B细胞和SLE发育中的无关作用，并将IRF7指向潜在的尽管最近对T1-IFN进行了临床试验，但仅与T1-IFN阻断疗法相比，SLE的治疗靶点更好受体阻塞疗法显示出令人鼓舞的结果。但是，我们对特定于细胞类型的角色一无所知尽管PDC在T1-IFN生产中的作用尚未确定，但IRF7在SLE开发中的作用良好。重要的是，b IRF7在自动反应性B细胞开发中通过外毛外抗体形成的细胞中性和 - 超支作用 SLE中的细胞（AFC）和卵泡生发中心（GC）途径尚不清楚。另外，独立于T1-IFN的IRF7 在SLE中的角色仍然未知。我们假设IRF7调节B细胞中的B细胞中心和t1-ifn-- AFC和GC途径中自动反应性B细胞发育中的依赖和非依赖性机制，导致致病性自身抗体产生和SLE。我们的初步数据支持了这一假设显示1）在AFCS（浆质/浆细胞），GC B细胞和髓样中的IRF7显着上调细胞2）增加了SLE患者活化B细胞中IRF7表达3）自身免疫性的急剧降低 AFC和GC的响应，自身抗体和免疫复合物沉积在sle-易于的FCGRIIB - / - 小鼠缺乏在IRF7 4）IRF7参与SLE易于B细胞中B细胞代谢活性改变并发表数据揭示5）IRF7在小鼠和人SLE中的作用。当前的提案将有助于确定B细胞中心 IRF7促进自动反应性B细胞和SLE发育的效力和机制，以及 IRF7是否可以比单独使用T1-IFN或T1-IFN受体阻塞更好的SLE治疗选择。