Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Division of Rheumatology, Department of Medicine, National University Hospital, Singapore, Singapore.
Front Immunol. 2022 Aug 9;13:957303. doi: 10.3389/fimmu.2022.957303. eCollection 2022.
Central nervous system (CNS) involvement of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE), is a major and debilitating manifestation of the disease. While patients with SLE mostly complain of common neuropsychological symptoms such headache and mild mood disorders that may not even be technically attributed to SLE, many SLE patients present with life-threatening NPSLE syndromes such as cerebrovascular disease, seizures and psychosis that are equally challenging in terms of early diagnosis and therapy. While we are just beginning to unravel some mysteries behind the immunologic basis of NPSLE, advancements in the mechanistic understanding of the complex pathogenic processes of NPSLE have been emerging through recent murine and human studies. The pathogenic pathways implicated in NPSLE are multifarious and various immune effectors such as cell-mediated inflammation, autoantibodies and cytokines including type I interferons have been found to act in concert with the disruption of the blood-brain barrier (BBB) and other neurovascular interfaces. Beyond antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. Activated neutrophils have been recognized to be involved in ischemic and infective processes in the CNS by releasing neutrophil extracellular traps (NETs), matrix metalloproteinase-9 and proinflammatory cytokines. In the context of NPSLE, these mechanisms contribute to BBB disruption, neuroinflammation and externalization of modified proteins on NETs that serve as autoantigens. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low-density neutrophils (LDNs) or low-density granulocytes. LDNs are a proinflammatory subset of neutrophils that are increased with SLE disease activity and are primed to undergo NETosis and release cytokines such as interferon-α and tumor necrosis factor. This review discusses the immunopathogenesis of NPSLE with a focus on neutrophils as a core mediator of the disease and potential target for translational research in NPSLE.
中枢神经系统（CNS）受累的系统性红斑狼疮（SLE），称为神经精神性狼疮（NPSLE），是该病的一种主要且使人虚弱的表现。虽然 SLE 患者大多抱怨常见的神经心理学症状，如头痛和轻度情绪障碍，这些甚至可能与 SLE 无关，但许多 SLE 患者出现危及生命的 NPSLE 综合征，如脑血管疾病、癫痫发作和精神病，这些疾病在早期诊断和治疗方面同样具有挑战性。虽然我们才刚刚开始揭开 NPSLE 免疫学基础背后的一些谜团，但通过最近的鼠类和人类研究，对 NPSLE 复杂发病机制的机制理解方面的进展已经出现。NPSLE 涉及的致病途径多种多样，细胞介导的炎症、自身抗体和细胞因子（包括 I 型干扰素）等各种免疫效应物已被发现与血脑屏障（BBB）和其他神经血管界面的破坏协同作用。除了抗菌功能外，中性粒细胞在先天和适应性免疫反应中也逐渐成为决策塑造者。已认识到激活的中性粒细胞通过释放中性粒细胞胞外陷阱（NETs）、基质金属蛋白酶-9 和促炎细胞因子参与 CNS 的缺血和感染过程。在 NPSLE 的背景下，这些机制导致 BBB 破坏、神经炎症和 NETs 上修饰蛋白的外化，这些蛋白作为自身抗原。在对血液进行密度离心后，沉降在外周血单核细胞部分的中性粒细胞通常被定义为低密度中性粒细胞（LDN）或低密度粒细胞。LDN 是一种促炎中性粒细胞亚群，随着 SLE 疾病活动增加而增加，并被预先激活以发生 NETosis 并释放干扰素-α和肿瘤坏死因子等细胞因子。本文综述了 NPSLE 的免疫发病机制，重点讨论了中性粒细胞作为疾病的核心介质以及 NPSLE 转化研究的潜在靶点。
