Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE

功能丧失的 NADPH 氧化酶变体对 SLE 中 B 细胞激活的影响

基本信息

批准号：
10577834
负责人：
Shaun William Jackson
金额：
$ 53.66万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
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：
2021-02-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577834
关键词：
Acceleration Adaptive Immune System Animals Antibodies Antigens Apoptotic Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity Autophagocytosis B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes Biochemical Cell Lineage Cell physiology Cells Chronic Complex Data Defect Development Disease Endosomes Event Exhibits Future Gene Deletion Generations Genes Genetic Models Genetic Polymorphism Genotype Goals Hematopoietic Human Human Genetics Immune Immune Tolerance Immune system Immunization Immunoglobulin Class Switching Immunologics In Vitro Individual Integrin alphaV Integrin alphaVbeta3 Integrins Investments Knockout Mice Ligands Link LoxP-flanked allele Lupus Maps Memory Modeling Mus Myelogenous Myeloid Cells NADPH Oxidase Nucleic Acid Regulatory Sequences Nucleic Acids Odds Ratio Organ Oxidases Pathogenesis Pathogenicity Pathway interactions Peripheral Blood Mononuclear Cell Phagocytes Phagocytosis Production Publishing Reactive Oxygen Species Receptor Signaling Regulation Regulator Genes Risk Signal Pathway Source Structure of germinal center of lymph node System Systemic Lupus Erythematosus T-Lymphocyte TLR7 gene Testing Tissues Toll-like receptors Untranslated RNA Variant Viral Antigens Virus Diseases Virus-like particle autoreactive B cell cellular imaging design disorder risk genetic variant genome wide association study humoral immunity deficiency imaging approach in vivo insight loss of function loss of function mutation new therapeutic target novel pathogenic autoantibodies prevent recruit response risk variant systemic inflammatory response targeted treatment trafficking

项目摘要

Project abstract Genome-wide association studies (GWAS) have identified immune pathways linked to the pathogenesis of systemic lupus erythematosus (SLE). However, despite these insights, our understanding of how individual genetic variants promote autoimmunity remains poor. Loss-of-function mutations in genes of the phagocytic NADPH oxidase complex (NOX2), including NCF1 and NCF2, have been linked with the pathogenesis of SLE and other humoral autoimmune diseases. The current model for how reduced NOX2 activity promotes lupus development focuses on defects in the clearance of apoptotic material by phagocytic myeloid lineages. While myeloid defects likely contribute to disease risk, we hypothesize that a parallel B cell-intrinsic mechanism underlies the profound increase risk of SLE in human carriers of NCF1 and NCF2 variants. In addition to the production of pathogenic autoantibodies, recent studies have demonstrated that B cells can promote lupus pathogenesis by initiating immune tolerance breaks and facilitating the generation of spontaneous germinal centers (GC). The activation of autoreactive B cells in SLE requires B cell-intrinsic expression of the endosomal toll-like receptors TLR7 and TLR9, and our published and preliminary data show that reduced NOX2 activity results in dysregulated endosomal TLR signaling by impacting non-canonical autophagy pathways. Based on these data, we hypothesize that a B cell-specific reduction in NOX2 activity will result in enhanced TLR- dependent GC formation and the development of humoral autoimmunity. We will test this idea via parallel in vivo and in vitro mechanistic studies. In Aim 1, we will test whether B cell-intrinsic deletion NOX2 component genes results in enhanced TLR-dependent GC responses using a well-characterized model of viral infection. In Aim 2, we will study whether reduced NOX2 activity promotes autoantibody production and humoral autoimmunity in murine SLE. Finally, in Aim 3, we will use biochemical and cell imaging approaches to test whether NAPDH oxidase activity impacts B cell TLR signaling and non-canonical autophagy pathways using both murine genetic models and gene-edited human B cells. Together, these studies promise to advance our understanding of lupus pathogenesis and may inform the design of future targeted therapies for human SLE.

项目摘要全基因组关联研究（GWAS）已经鉴定出与与全身性红斑狼疮（SLE）。但是，尽管有这些见解，但我们对个人的理解遗传变异促进自身免疫性仍然很差。吞噬细胞基因的功能丧失突变 NADPH氧化酶复合物（NOX2），包括NCF1和NCF2，已与SLE的发病机理联系在一起和其他体液自身免疫性疾病。减少NOX2活性如何促进狼疮的当前模型发展侧重于吞噬髓样谱系清除凋亡材料的缺陷。尽管髓样缺陷可能导致疾病风险，我们假设是平行的B细胞内部机制在NCF1和NCF2变体的人类载体中，SLE的巨大风险是基础。除了致病自身抗体的产生，最近的研究表明，B细胞可以促进狼疮通过发起免疫耐受性破裂并促进自发生发产生的发病机理中心（GC）。 SLE中自动反应性B细胞的激活需要内体的B细胞内膜表达 Toll样受体TLR7和TLR9，以及我们发布的和初步的数据表明，NOX2活动降低了通过影响非典型自噬途径，导致内体TLR信号传导失调。基于这些数据，我们假设NOX2活性的B细胞特异性降低将导致TLR- 依赖的GC形成和体液自身免疫的发展。我们将通过平行体内测试这个想法和体外机械研究。在AIM 1中，我们将测试B细胞中缺失NOX2分量基因是否通过使用良好的病毒感染模型来增强TLR依赖性GC反应。在AIM 2中，我们将研究减少的NOX2活性是否促进自身抗体的产生和体液自身免疫性鼠sle。最后，在AIM 3中，我们将使用生化和细胞成像方法测试NAPDH是否氧化酶活性会影响B细胞TLR信号传导和非典型自噬途径使用两种鼠遗传模型和基因编辑的人类B细胞。这些研究共同有望提高我们对狼疮的理解发病机理，可能会为人类SLE的未来靶向疗法设计。