Low density neutrophils and lupus

低密度中性粒细胞和狼疮

• 批准号: 10743175
• 负责人: Carol F Webb
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-08 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10743175
• 关键词: ATAC-seq; Affect; Antigen-Antibody Complex; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Binding Sites; Blood Cells; Cell Line; Cells; Characteristics; Chemotaxis; Chromatin; Clinical; Clinical Trials; Co-Immunoprecipitations; Complex; Cytokine Signaling; DNA-Binding Proteins; Data; Dendritic Cells; Development; Disease; Epigenetic Process; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Growth Factor; Heterogeneity; Human Herpesvirus 4; Immune response; Impairment; Individual; Inflammatory; Interferon alpha; Kidney; Knowledge; Laboratories; Lupus; Maintenance; Mass Spectrum Analysis; Mediator; MicroRNAs; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytosis; Phenotype; Predisposition; Production; Proteins; Publishing; Receptor Signaling; Regulatory Pathway; Sorting; Symptoms; Systemic Lupus Erythematosus; Technology; Testing; Tissue-Specific Gene Expression; Transgenic Mice; Treatment Protocols; Validation; body system; constitutive expression; cytokine; density; differential expression; effective therapy; experimental study; extracellular; granulocyte; indexing; individual patient; inhibitor; neutrophil; new therapeutic target; novel; overexpression; pathogen; posttranscriptional; protein expression; success; therapeutic target; transcriptome sequencing

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems and for which current treatments are toxic and impair immune responses to pathogens, so new treatment regimens are needed. Identification of new therapeutic targets is complicated by a lack of understanding of the mechanisms that cause SLE. ARID3a is a DNA-binding protein that can alter gene expression both at the transcription level, and by contributing to epigenetic landscapes. We found that ARID3a protein is expressed in low density neutrophils (LDNs) of SLE patients, but not in LDNs from healthy controls, and ARID3a expression was associated with production of the inflammatory cytokine, interferon alpha (IFNα) in the same cells. Surprisingly, increased numbers of ARID3a+ LDNs are more significantly associated with increased disease activity indices (SLEDAI scores; R2=0.65) in SLE patients than were numbers of IFNα-producing LDNs. These data suggest that ARID3a-expressing LDNs contribute to disease activity in SLE through other mechanisms than IFNα production. Our previous data suggested that ARID3a protein expression was associated with differential gene expression patterns in LDNs. We hypothesize that ARID3a-associated gene dysregulation contributes to SLE disease pathogenesis. Therefore, our first aim is to define binding sites for ARID3a near differentially expressed genes and accessible epigenetic domains in SLE. The second specific aim will directly test known functions of LDNs to define which of those functions require ARID3a expression and which may be inhibited with ARID3a-specific inhibitors. Finally, we found that ARID3a expression in LDNs is not regulated at the level of transcription, perhaps explaining why ARID3a has not been previously identified through elegant RNA-seq studies as potential driver of pathogenesis in SLE LDNs. Our third aim will determine how ARID3a protein expression is induced in LDNs. Our published and preliminary data support the idea that ARID3a contributes to, or is a consequence of, disease activity in SLE and that inhibition of ARID3a decreases autoimmune symptoms. These experiments will fill important gaps in our understanding of how ARID3a is associated with SLE and will define functions and genetic pathways that may serve as new therapeutic targets for this devastating disease.

摘要 系统性红斑狼疮(SLE)是一种影响多器官系统的复杂自身免疫性疾病 而目前的治疗方法是有毒的，会损害对病原体的免疫反应，所以新的治疗方法 养生法是必要的。由于缺乏对治疗靶点的了解，新的治疗靶点的确定变得复杂 导致系统性红斑狼疮的机制。ARID3a是一种DNA结合蛋白，可以改变基因表达 转录水平，并通过对表观遗传景观的贡献。我们发现ARID3a蛋白在 SLE患者低密度中性粒细胞(LDN)，而健康对照组LDN不表达，以及ARID3a表达 与炎症细胞因子--干扰素α在同一细胞中的产生有关。 令人惊讶的是，ARID3a+LDN的数量增加与疾病增加有更显著的相关性 系统性红斑狼疮患者的活动性指数(SLEDAI评分；R2=0.65)大于产生干扰素α的LDN数量。这些 数据表明，表达ARID3a的LDN通过其他机制促进SLE的疾病活动 比干扰素α的产量高。我们先前的数据表明，ARID3a蛋白的表达与 低密度脂蛋白的差异基因表达模式。我们假设ARID3a相关基因失调 参与了SLE疾病的发病机制。因此，我们的第一个目标是定义ARID3a在 系统性红斑狼疮差异表达基因和可获得的表观遗传域。第二个具体目标将直接 测试LDN的已知函数，以定义这些函数中哪些需要ARID3a表达式，哪些可能 用ARID3a特异性抑制剂抑制。最后，我们发现在低密度脂蛋白中ARID3a的表达不受 转录水平，也许解释了为什么以前没有通过Eraise RNA-SEQ研究是SLE LDNS发病机制的潜在驱动因素。我们的第三个目标将决定ARID3a如何 在低密度脂蛋白中诱导蛋白质表达。我们公布的和初步的数据支持ARID3a 导致SLE疾病活动或是其结果，ARID3a的抑制作用减弱 自身免疫性症状。这些实验将填补我们对ARID3a是如何 与系统性红斑狼疮相关，并将定义可能作为新的治疗靶点的功能和遗传途径 对这种毁灭性的疾病负责。