Project 1: Profiling anti-Ro preclinical and clinical autoimmunity

项目 1：分析抗 Ro 临床前和临床自身免疫

• 批准号: 10004505
• 负责人: ROBERT M CLANCY
• 金额: $ 29.69万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004505
• 关键词: Adaptive Immune System; Address; Alleles; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Benign; Birth; CD4 Positive T Lymphocytes; Cellular Immunity; Cellular Metabolic Process; Child; Clinical; Communities; Complex; Data; Deoxyribonucleases; Development; Disease; Disease Progression; Environment; Evaluation; Fetal Development; General Population; Genetic; Genetic Variation; Genotype; Gut associated lymphoid tissue; Haplotypes; Immune response; Immune system; Immunoglobulin A; Individual; Inherited; Interferon Type II; Interleukin-2; Intestines; Investigation; Lupus; Maintenance; Molecular; Molecular Profiling; Mothers; Neonatal lupus erythematosus; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Peptides; Phenotype; Photosensitivity; Play; Populations at Risk; Positioning Attribute; Probability; Production; Property; Public Health; Registries; Research; Response Elements; Rest; Rheumatism; Risk; Role; SS-A antibodies; Secretory Immunoglobulin A; Serological; Surveys; Susceptibility Gene; Symptoms; Systemic Lupus Erythematosus; Systems Development; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; Testing; Time; Traction; Variant; Woman; base; benign state; biomarker discovery; cohort; commensal microbes; cross reactivity; fecal microbiome; gene interaction; genetic profiling; gut microbiome; gut microbiota; interest; longitudinal analysis; microbial; microbiome; microorganism; mimicry; next generation sequencing; offspring; pathobiont; pre-clinical; predictive marker; prevent; risk variant; synergism; theories; tissue injury

ABSTRACT Mounting evidence suggests that autoantibodies can antecede overt clinical disease, with anti-SSA/Ro among the earliest reactivities. Yet, predicting who remains protected from overt disease or who will progress would be a game-changing discovery for understanding the pathogenesis of Systemic Lupus Erythematosus (SLE). Mothers in the Research Registry for Neonatal Lupus (RRNL) represent a unique population at risk for overt clinical autoimmunity. Despite the presence of high titer anti-Ro antibodies potentially pathogenic to the developing fetus, many women are asymptomatic, with autoimmunity identified solely based on disease in their offspring. Currently, of 521 RRNL mothers, 283 were asymptomatic, or had only minimal symptoms, at the time of the birth of the NL child, whereas a subset developed SLE. The intertwining of genetic variation in the HLA locus with the capacity to undergo shifts toward a pathologic gut microbiome may, in part, explain progression from benign to pathologic autoimmunity and overt SLE. Alternatively, other HLA variants may instead associate with a protective microbiome that halts progression so that a state of benign autoimmunity persists. In Specific Aim 1, associations will be sought between host genetics and anti-Ro NL disease status. We will genotype an estimated 297 RRNL mothers using an HLA next generational sequencing approach that makes no a priori sequence assumptions. The HLA alleles will be informative to distinguish asymptomatic anti-Ro-mothers (particularly those remaining so for >6 years) from those who initially or quickly progressed to classified SLE. In Specific Aim 2, associations will be sought between gut microbiome taxa in the context of HLA and anti-Ro NL maternal disease status, as we address the hypothesis that HLA is a central driver of pathobiont associations that contribute to the pathogenesis of overt SLE. A planned longitudinal analysis of the asymptomatic RRNL mothers will be highly informative and expected to capture women who transition to established SLE. In Specific Aim 3, we will elucidate the relationships of serological and cellular immunity (and CD4 T-cell subsets) and anti-Ro NL maternal disease status. Newly generated data will be continuously shared and discussed with Drs. Silverman (Project 2) and Reizis (Project 3) to further explore associations in the context of circulating and fecal IgA and anti-DNASE1L3 sensitive reactivity with microparticles. A molecular basis for the specific microbial taxa that are coated with sIgA will be evaluated in context of a mimicry hypothesis that considers cross-reactivity between T cell epitopes and bacterial peptides. From a public health perspective, it is anticipated that conserved patterns or blueprints will be identified for host immune systems that are best suited to arrest autoimmunity at a benign preclinical state or conversely that favor progression to overt SLE and tissue injury. Identification of one or more predictive biomarkers that associate with a persistently asymptomatic state could also serve as the “target to achieve” while a permissive factor might represent a “target to inhibit” in an established SLE patient.

摘要 越来越多的证据表明，自身抗体可以先于明显的临床疾病，抗SSA/Ro是其中之一 最早的反应。然而，预测谁仍然免受显性疾病的影响，或者谁会进步，将会 对于了解系统性红斑狼疮(SLE)的发病机制来说，这是一个改变游戏规则的发现。 新生儿狼疮研究登记处(RRNL)中的母亲代表了一个独特的显性高危人群 临床自身免疫性疾病。尽管存在可能致病的高滴度抗Ro抗体 在发育中的胎儿中，许多妇女没有症状，自身免疫仅根据她们体内的疾病来确定 后代。目前，在521名RRNL母亲中，283人当时没有症状或只有轻微症状 NL儿童的出生，而一个子集则发展为SLE。人类白细胞抗原基因变异的相互交织 具有向病理性肠道微生物群转移的能力的基因座可能在一定程度上解释了疾病进展 从良性到病理性自身免疫和明显的系统性红斑狼疮。或者，其他的人类白细胞抗原变异体可以改为关联 具有保护性的微生物群可以阻止病情发展，因此良性自身免疫状态持续存在。具体而言 目的1，寻找宿主遗传学与抗Ro-NL病状态之间的联系。我们将对一个人进行基因分析 估计297名RRNL母亲使用无先验的人类白细胞抗原下一代测序方法 顺序假设。人类白细胞抗原等位基因将有助于区分无症状的抗-RO母亲 (特别是那些保持了6年的人)，来自那些最初或很快发展为分类的SLE的人。在……里面 具体目标2，将在人类白细胞抗原和抗-Ro的背景下寻找肠道微生物类群之间的联系 NL母体疾病状态，因为我们解决了人类白细胞抗原是致病因素的中心驱动因素的假说 与临床系统性红斑狼疮发病相关的因素。计划中的纵向分析 无症状的RRNL母亲将具有高度的信息量，预计将捕捉到过渡到 确诊为系统性红斑狼疮。在具体目标3中，我们将阐明血清学和细胞免疫之间的关系。 (和CD4T细胞亚群)和抗Ro-NL母体疾病状况。新生成的数据将持续 与Silverman博士(项目2)和Reizis博士(项目3)分享和讨论，以进一步探索 循环和粪便中的IgA和抗DNASE1L3抗体与微粒的敏感反应。一种分子 包被SIGA的特定微生物分类群的基础将在模拟实验的背景下进行评估 考虑T细胞表位和细菌肽之间交叉反应的假说。从公共卫生角度来看 从长远来看，预计将确定宿主免疫系统的保守模式或蓝图。 最适合在良性临床前状态下阻止自身免疫，或者相反，有利于进展到 明显的系统性红斑狼疮和组织损伤。识别与一个或多个预测生物标志物相关联的 持续的无症状状态也可以作为“要实现的目标”，而允许的因素可能是 代表了已确诊的系统性红斑狼疮患者的“抑制靶点”。