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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