Mechanisms of New-Onset Autoimmunity/Longitudinal Immune Systems Analysis (MONA-LISA)

项目总结/摘要 新发自身免疫的机制-纵向免疫系统分析（MONA-LISA）将使用 临床试验（抗疟疾药物研究）进行期间获得的临床数据和生物标本 不完全性红斑狼疮（SMILE，NCT 03030118），以研究 促使无症状或症状轻微的自身免疫个体得到明确诊断 系统性红斑狼疮这些数据和标本是一个独特的资源，代表纵向 临床评估、患者报告结局、DNA、RNA、血清、血浆、外周血单核细胞 在从不完全进展之前、期间和之后以标准化方式获得的细胞和尿液 红斑狼疮到系统性红斑狼疮（SLE）-观察发生在20 %的SMILE参与者可用于研究。研究的总体目标是了解 进展为SLE的个体中存在潜在的免疫学、基因组和代谢差异 与那些没有取得进展的目标相比，开发更好的诊断和预后工具， 健康护理提供者以及描述新的治疗靶点，使得具有早期特征的个体 可以防止自身免疫发展为器官损伤和残疾的状态。 MONA-LISA的具体目的包括：1）获得外周血淋巴细胞的全面、多重分析 使用新的137-plex方法对SMILE队列中的进展者和非进展者进行血液免疫表型分析 CITE-seq分析、sn-ATAC-seq、sc-RNA-seq以及T和B细胞库测定，以产生稳健的， 这些个体的PBMC中的细胞特异性mRNA和表观基因组谱的定量图谱。2)执行 靶向基因组测序，对SLE风险基因座的调控和结构变异进行分类， 转录组学和表观基因组学数据，并创建基于基因调控的新风险评估。3)探索 血浆和血清代谢和脂质成分，可以作为新的特征，分类的风险， 向狼疮分类进展的SMILE参与者。4)最后，由于SMILE注册人数较少， 黑人个体比在流行性狼疮患者的流行病学代表，我们将执行一个 集中招募非欧洲ILE患者，并比较他们的多组学特征， 目的1-3中描述的免疫表型。这将使更完整和更普遍的结论， 在种族群体中绘制，并确定自身免疫风险的任何祖先特异性变化 可以解释狼疮流行病学中观察到的差异的进展。完成后，MONA-LISA 将为研究人员和医疗保健提供者提供更好的工具来预测谁会患上狼疮， 更有效的疾病预防干预试验。

PROJECT SUMMARY/ABSTRACT The Mechanisms of New-Onset Autoimmunity-Longitudinal Immune Systems Analysis (MONA-LISA) will use clinical data and biospecimens obtained during performance of the clinical trial, Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE, NCT03030118) to investigate immunological mechanisms that propel individuals who have asymptomatic or minimally symptomatic autoimmunity towards a definite diagnosis of systemic lupus erythematosus. These data and specimens are a unique resource, representing longitudinal clinical assessments, patient-reported outcomes, DNA, RNA, serum, plasma, peripheral blood mononuclear cells and urine obtained in a standardized manner before, during, and after the progression from Incomplete Lupus Erythematosus to Systemic Lupus Erythematosus (SLE) – an observation that occurred in twenty percent of the SMILE participants available for study. The overall objective of the study is to learn the underlying immunological, genomic, and metabolic differences present in individuals who progress to SLE compared to those that do not progress with goals to both develop better diagnostic and prognostic tools for health care providers as well as describe novel therapeutic targets so that individuals with early features of autoimmunity can be prevented from progressing to a state of organ damage and disability. The Specific Aims of MONA-LISA include: 1) Obtain a comprehensive, multiplex analysis of the peripheral blood immunophenotype of progressors and non-progressors in the SMILE cohort using a novel 137-plex CITE-seq analysis, sn-ATAC-seq, sc-RNA-seq and T and B cell repertoire determination to create a robust, quantitative atlas of cell-specific mRNA and epigenomic profiling in PBMC of these individuals. 2) Perform targeted genomic sequencing to categorize regulatory and structural variants of SLE risk loci to tie together the transcriptomic and epigenomic data and create novel risk assessments based on gene regulation. 3) Explore plasma and serum metabolic and lipid components that can serve as novel features that classify the risk of SMILE participants who progress towards classification with lupus. 4) Lastly, because SMILE enrolled fewer Black individuals than are represented in the epidemiology of prevalent lupus patients, we will perform a focused recruitment of non-European individuals with ILE and compare their multi-omic characterization of immunophenotypes described in Aims 1-3. This will allow more complete and generalizable conclusions to be drawn across ethnic groups and identify any ancestry-specific variations in the risk of autoimmunity progression that can explain the observed differences in lupus epidemiology. When completed, MONA-LISA will provide researchers and health care providers with better tools to predict who will develop lupus and create more effective interventional trials for disease prevention.