Plasma cell differentiation of autoreactive B cells is governed by TLR9 dependent metabolic reprogramming

自身反应性 B 细胞的浆细胞分化受 TLR9 依赖性代谢重编程控制

基本信息

批准号：
9979450
负责人：
Kerstin Nündel
金额：
$ 18.43万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979450
关键词：
American Animal Model Anti-Inflammatory Agents Antibodies Antigen-Antibody Complex Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process B cell differentiation B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Biochemical Pathway Biological Assay Cell Death Cell physiology Cells Citric Acid Cycle Clinical DNA DNA Binding Data Defect Development Disease Etiology Event Family member Flow Cytometry Genes Genus Hippocampus Glucose Glycolysis Homeostasis IL6 gene Immune In Vitro Inbred MRL lpr Mice Inflammatory Interleukin-10 Interleukin-12 Investigation Lead Link Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Metformin Mitochondria Modeling Mus Nucleic Acid Binding Oxidative Phosphorylation Oxygen Consumption Pathway interactions Pharmacology Plasma Cells Play Production RNA RNA Binding Receptors, Antigen, B-Cell Regulation Reporting Respiration Risk Factors Role Signal Pathway Signal Transduction Study models Symptoms Systemic Lupus Erythematosus TLR4 gene TLR7 gene TLR9 gene Testing Therapeutic Toll-like receptors anti-dsDNA autoantibody autoreactive B cell base cell type crosslink cytokine immunoregulation in vivo insight macrophage mitochondrial dysfunction mouse model new therapeutic target novel plasma cell differentiation prevent protective effect sensor systemic autoimmune disease transcription factor

项目摘要

ABSTRACT SLE is a devastating systemic autoimmune disease of unknown etiology that presents with a diverse array of clinical symptoms and afflicts over 1.5 million Americans. Numerous risk factors have been identified, and it is generally accepted that SLE can result from a spectrum of immunoregulatory defects. However, one of the key events is a breach in tolerance of autoreactive B cells and their development into autoantibody producing plasma cells. Nucleic acid binding Toll-like receptors (TLRs) have been found to play a critical role in the production of autoantibodies and disease development in all animal models of SLE that have been examined to date. Intriguingly, in these same models, TLR9 appears to play both a protective and disease promoting role;; TLR9 is required for the production of anti-dsDNA autoantibodies, but surprisingly, TLR9KO autoimmune-prone mice develop much more severe clinical disease than their TLR9-sufficient counterparts. Previously, we have reported that activation of autoreactive B cells with TLR9 dependent DNA-containing immune complexes causes rapid proliferation followed by cell death while activation with TLR7 dependent RNA-containing immune complexes leads to plasma cell differentiation. The exact basis for this bifurcation in B cell differentiation is still under investigation. We have preliminary evidence that TLR9 uniquely regulates the NF-kB pathway by promoting IkBa degradation and expression of IkBz. IkBz is an important transcription factor that regulates the levels of pro-inflammatory (IL6, IL12) and anti-inflammatory cytokines (IL10). Recently, the expression of IkBz has been linked to the immunometabolite itaconate. Interestingly, TLR9KO B cells show a decreased oxygen consumption rate compared to WT B cells after immune complex activation suggesting a role for TLR9 in the regulation of metabolism. Putting these findings together, we hypothesis that TLR9 plays a key role in metabolic reprogramming of autoreactive B cells and subsequent modulation of important signaling pathways. In Aim 1, we will explore the role of TLR9 in increasing cellular metabolism in immune complex activated B cells and its inhibitory effect on plasma cell differentiation. In Aim 2, we will explore the pathways by which TLR9 dependent metabolic reprogramming modulates the NF-kB pathway downstream of B cell receptor crosslinking. Based on our hypothesis, we expect to identify key roles for itaconate and IkBz in plasma cell differentiation. Overall, the studies outlined in this application should provide important insights regarding the metabolic requirements of autoreactive B cells and its influence on B cell fate decisions. The findings from these studies may lead to the discovery of new therapeutic targets for SLE.

抽象的 SLE是一种毁灭性的系统性自身免疫性病因，其病因呈现多种临床症状和150万美国人的症状。接受SLE可以由一系列免疫调节缺陷产生。耐受性B细胞的耐受性及其发展为自身抗体产生浆细胞。酸结合收费受体（TLR）在自身抗体的产生中起着至关重要的作用迄今为止，所有动物模型的疾病发展都在研究中。模型，TLR9似乎扮演着保护性和疾病的作用；抗DSDNA自身抗体，但令人惊讶的是，TLR9KO自身免疫性免疫性小鼠小鼠会发展出更严重的临床疾病比其TLR9-SuffFffication对应物。含有TLR9的含DNA免疫复合物会导致细胞死亡的快速增殖，而 Activation with TLR7 Dependent RNA-CONTAING IMMUNE COMUNE COMUNE COMUNE COMUNE COMUNE COMPLEXES to Plasma Cell Difference. The EXACT B细胞分化中的分叉基础仍在研究中。通过促进IkbaBz的ikba降解和表达来独特地调节NF-KB途径。转录因子定于促炎物的水平（IL6，IL12）和抗炎细胞因子（IL10）。最近，Ikbz的表达与免疫代谢物息肉相关。与WT B细胞相比，在免疫复合激活后显示出氧的消耗率降低，表明A TLR9在代谢调节中的作用。在自动反应性B细胞的代谢重编程以及随后对重要信号通路的调节中的作用。在AIM 1中，我们将探讨TLR9在增加细胞代谢中的作用它对AIM 2的抑制作用对浆细胞的分化。代谢复印机将基于我们的B细胞受体交联的NF-KB途径假设，我们期望确定Itaconate和Ikbz在浆细胞区分中的关键作用本应用程序中概述的应提供有关自动反应性代谢要求B的重要见解细胞及其对B细胞命运决策的影响。新的新新新。 SLE的治疗靶标。