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

系统性红斑狼疮(SLE)是一种具有毁灭性影响的多系统自身免疫性疾病，一旦确诊，将是永久性的。免疫抑制治疗会带来改善，但需要终生服药，具有累积的毒性和损害。我的工作提出了一种全新的范式，基于对即将到来的疾病的预测，在疾病不可逆转之前进行预测，并为该阶段提供新的治疗靶点。洞察1：系统性红斑狼疮是由无症状自身免疫(自身抗体阳性)逐步产生的。通过前瞻性地研究一个独特的“高危”队列，我发现在大多数患者保持健康的动态平衡中，存在严重的免疫功能障碍。然而，I型干扰素途径激活(IFN-I)预测进展为SLE，数据表明还有其他潜在的临床、遗传和免疫表型预测因素。在炎症或治疗之前，由于角质形成细胞持续产生干扰素-I，循环中的干扰素-I来源出现缺陷；这是对标准范式的逆转，即系统性红斑狼疮是由白细胞攻击正常组织引起的。因此，以前被认为是“靶器官”的组织实际上可能在SLE的发生和维持中发挥积极作用。这可能解释系统性红斑狼疮的耐药性，并提供新的药物靶点。我将在这一战略愿景的基础上，扩大这些高危人群，以利用一系列尖端方法来(I)准确识别生物标记物和临床风险模型，高危个体将发展成SLE(Ii)使用最先进的方法和对朗格汉斯细胞的关注来理解为什么免疫过程可能仍然局限于皮肤或进展为全身自身免疫，；(Iii)用单细胞RNAseq并行分析循环免疫细胞，重点放在B细胞和髓系细胞上。这项工作将有助于更好地理解高危个体的发病机制和预防性治疗的试验：防止自身免疫的长期抱负的一步改变。

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.