Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Nature. 2017 Jun 22;546(7659):539-543. doi: 10.1038/nature22821. Epub 2017 Jun 14.
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
系统性红斑狼疮（SLE）是一种无法治愈的自身免疫性疾病，其特征是在肾脏、皮肤和肺部等组织中沉积自身抗体。值得注意的是，高达 75%的 SLE 患者出现神经精神症状，从焦虑、抑郁和认知障碍到癫痫发作，在极少数情况下还会出现精神病——统称为中枢神经系统（CNS）狼疮。在某些情况下，某些自身抗体，如抗 NMDAR 或抗磷脂抗体，会促进 CNS 狼疮。然而，在大多数患者中，这些症状的发生机制尚不清楚。CNS 狼疮通常在狼疮诊断时或在发病的第一年出现，这表明导致外周自身免疫的早期因素可能会促进 CNS 狼疮症状的出现。在这里，我们报告了狼疮易感小鼠的行为表型和突触丧失，这些表型和丧失可以通过阻断 I 型干扰素（IFN）信号来预防。此外，我们还表明，I 型 IFN 刺激小胶质细胞变得活跃，并在狼疮易感小鼠中吞噬神经元和突触物质。这些发现以及我们观察到 SLE 患者死后海马脑区的 I 型 IFN 信号增加，可能会指导正在进行的 anifrolumab（一种 I 型 IFN 受体拮抗剂）临床试验的评估。此外，IFN 驱动的小胶质细胞依赖性突触丧失的鉴定，以及小胶质细胞转录组数据，将 CNS 狼疮与其他 CNS 疾病联系起来，并为一些 SLE 患者出现的神经症状提供了解释。
