Project 1: Profiling anti-Ro preclinical and clinical autoimmunity

摘要 越来越多的证据表明，自身抗体可以提前明显的临床疾病，其中抗SSA/Ro 最早的反应。然而，预测谁仍然免受显性疾病的影响或谁将取得进展， 是一个改变游戏规则的发现，了解系统性红斑狼疮（SLE）的发病机制。 新生儿狼疮研究登记处（RRNL）的母亲代表了一个独特的人群， 临床自身免疫尽管存在高滴度的抗Ro抗体，但其可能对 在胎儿发育过程中，许多妇女是无症状的，自身免疫性仅根据其 后代目前，在521名RRNL母亲中，283名当时没有症状，或只有轻微症状 出生的NL儿童，而一个子集开发SLE。HLA中遗传变异的交织 具有向病理性肠道微生物组转变的能力的基因座可以部分解释疾病进展 从良性到病理性自身免疫和显性SLE。或者，其他HLA变异体可能与 有一个保护性的微生物组，阻止进展，使良性自身免疫状态持续存在。在特定 目的1，将寻求宿主遗传学和抗Ro NL疾病状态之间的关联。我们将对一个 使用HLA下一代测序方法估计了297名RRNL母亲， 序列假设HLA等位基因将提供信息，以区分无症状的抗Ro-母亲 （特别是那些保持这种状态>6年的患者）与最初或迅速进展为分类的SLE的患者相比。在 具体目标2，将在HLA和抗Ro背景下寻找肠道微生物组分类群之间的关联 NL母体疾病状态，因为我们解决了HLA是致病菌的中心驱动力的假设， 与显性SLE发病机制有关。计划中的纵向分析 无症状RRNL母亲将提供大量信息，并有望捕获过渡到 建立SLE。在具体目标3中，我们将阐明血清学和细胞免疫的关系 (and CD 4 T细胞亚群）和抗Ro NL母体疾病状态。新生成的数据将持续 与Silverman博士（项目2）和Reizis博士（项目3）分享并讨论，以进一步探索 循环和粪便伊加和抗DNASE 1 L3与微粒的敏感反应性的背景。分子 将在模拟的背景下评估用sIgA包被的特定微生物分类群的基础 这一假说考虑了T细胞表位和细菌肽之间的交叉反应性。从公共卫生 从这一角度来看，预计将确定宿主免疫系统的保守模式或蓝图 最适合于在良性临床前状态下阻止自身免疫，或者相反，有利于进展为 明显的SLE和组织损伤。鉴定与肿瘤相关的一种或多种预测性生物标志物 持续无症状的状态也可以作为“实现的目标”，而允许的因素可能 在确定的SLE患者中代表“抑制的靶标”。

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.