PREVENT-SLE: Towards PREdiction and preVENTion of Systemic Lupus Erythematosus

系统性红斑狼疮（SLE）是一种多系统的自身免疫性疾病，具有破坏性的影响;一旦确诊，它是永久性的。免疫抑制治疗可以改善病情，但需要终身用药，并具有累积毒性和损伤。从我的工作中获得的见解提出了一个全新的范式，该范式基于在疾病不可逆之前预测即将发生的疾病和该阶段的新治疗靶点。见解1：SLE由无症状的自身免疫（自身抗体阳性）逐步引起。通过前瞻性研究一个独特的“高危”队列，我发现在一个动态平衡中，大多数患者保持健康，存在严重的免疫功能障碍。然而，I型干扰素通路激活（IFN-I）可预测SLE的进展，数据表明还有其他潜在的临床、遗传和免疫表型预测因子。在炎症或角质形成细胞持续产生IFN-I进行治疗之前，IFN-I的循环来源就会出现缺陷;这与SLE是由白细胞攻击正常组织引起的标准范式相反。因此，以前被认为是“靶器官”的组织实际上可能在SLE的发生和维持中起着积极的作用。这可能解释SLE的耐药性并提供新的药物靶点。我将基于这一战略愿景，扩展这些高危人群，利用一系列尖端方法（i）准确识别具有生物标志物和临床风险模型的高危个体将发展SLE（ii）使用最先进的方法和对朗格汉斯细胞的关注，以了解为什么免疫过程可能仍然局限于皮肤或进展为全身性自身免疫;（iii）同时使用单细胞RNAseq分析循环免疫细胞，重点是B细胞和骨髓细胞。这项工作将有助于提高对发病机制的理解，并在高危人群中进行预防性治疗试验：这是预防自身免疫的长期目标的一步变化。

Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease with devastating impact; once diagnosed it is permanent. Immunosuppressive therapy leads to improvement, but lifelong medication is needed, with cumulative toxicity and damage. Insights from my work suggests a radically new paradigm based on prediction of imminent disease before it is irreversible and novel therapeutic targets for that phase.Insight 1: SLE arises from asymptomatic autoimmunity (auto-antibody positive) in a stepwise fashion. By prospectively studying a unique "At-Risk" cohort, I found profound immune dysfunction in a dynamic equilibrium in which most patients remain healthy. However, type I interferon pathway activation (IFN-I) predicted progression to SLE, and data suggest there are other potential clinical, genetic and immunophenotypic predictors.Insight 2:. Circulating sources of IFN-I become defective before inflammation or therapy with sustained production of IFN-I by keratinocytes; this is a reversal of the standard paradigm that SLE is caused by leucocytes attacking normal tissues. Therefore, tissues previously regarded as "target organs" may actually play an active role in initiation and maintenance of SLE. This may explain the resistance of SLE and offer new drug targets.I will build on this strategic vision to extend these At-Risk cohorts to leverage a series of cutting edge methods to (i) accurately identify with biomarkers and a clinical risk model which At-Risk individuals will develop SLE (ii) use state of the art methods and a focus on Langerhans cells to understand why immune processes may remain confined to the skin or progress to systemic autoimmunity,; (iii) in parallel analyse circulating immune cells with single-cell RNAseq focussing on B cells and myeloid cells.This work will lead to improved understanding of pathogenesis and trials of preventative therapies in high risk individuals: a step change in the longstanding ambition to prevent autoimmunity.