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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.

摘要：系统性红斑狼疮是一种具有毁灭性的、全身性和自身免疫性疾病，其病因不明，呈现出一系列极其多样化的临床疾病。症状和疾病困扰着超过150万美国人。尽管无数的风险因素尚未被识别，但它是普遍存在的。公认的观点是，系统性红斑狼疮可能是由于一系列免疫调节系统缺陷造成的。然而，在所有关键的免疫事件中，有一项是未知的。突破了对自身反应性B细胞的耐受性，并使其发育成为一种自身抗体，从而产生更多的浆细胞。已有研究发现，酸性结合蛋白-Toll样受体受体(TLRs)在体内自身抗体的产生过程中发挥着至关重要的作用。疾病和疾病的发展在迄今为止还没有被研究过的所有系统性红斑狼疮的动物模型中都存在。有趣的是，在这些模型中也是如此。 ;的TLR9似乎既是一种保护性疾病，也是一种疾病的促进者；TLR9的TLR9似乎是汽车的主要生产方式所必需的。抗dsDNA是自身抗体，但令人惊讶的是，TLR9KO是容易产生自身免疫的小鼠，临床上会患上更严重的疾病。疾病比他们的TLR9足够多。但在以前，我们已经报道过，他们的自身反应性B细胞的激活速度。由于TLR9依赖于含DNA的免疫球蛋白复合体，导致细胞快速增殖，紧随其后的是细胞死亡。通过激活TLR7依赖的含RNA的免疫球蛋白复合体，可以促进血浆和细胞的分化。这种B细胞分化障碍的基础仍在调查中。我们有初步的证据表明，TLR9。通过促进IkBZ的降解和表达，独特地调节了Ik-nkB途径。Ik Ik BZ BZ是一个非常重要的因素。转录因子是一种调节促炎症因子(IL6，IL12)和抗炎因子(IL10)水平的因子。最近，IkBZ的基因表达被证实与免疫代谢产物衣康酸有关。有趣的是，TLR9KO与B细胞有关。显示在免疫调节复合体激活后，与WT-B细胞相比，其氧耗率明显下降，这表明这是一种新的治疗方法。 TLR9基因在机体代谢的主要调控过程中的作用。将这些研究结果综合在一起，我们提出了一种假说，即TLR9基因在机体代谢中起着关键作用。在自身反应性B细胞的代谢和重新编程过程中发挥作用，以及随后对一些重要的信号转导通路进行信息调制。在目标1中，我们将进一步探索TLR9基因在提高免疫复合物激活的B细胞中的细胞免疫代谢水平中的重要作用。它对血浆和细胞分化的抑制作用。在我们的目标2中，我们将进一步探索TLR9依赖的新的途径。新陈代谢和重新编程调节核因子-B受体的下游通路和B细胞受体的交联性。假设，我们可以期待他们能够确定Itaconate和IkBZ在血浆和细胞分化中的关键作用。总体而言，这两项研究。在本申请中概述的内容应提供关于自动反应B的主要代谢物要求的更重要的信息见解。细胞及其对B细胞命运和决策的影响。从这些研究中得出的新发现可能会导致我们发现一种新的细胞。治疗系统性红斑狼疮的目标是治疗。