Correspondence on 'Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment'.
Correspondence on 'Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment'.
复制标题
关于“系统性红斑狼疮的血脑屏障渗漏与灰质损失和认知障碍相关”的通讯。
DOI：
10.1136/annrheumdis-2021-220031
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发表时间：
2021
影响因子：
27.4
通讯作者：
Hasni,Sarfaraz
中科院分区：
文献类型：
--
作者：
Pamuk,OmerNuri;Hasni,Sarfaraz
我们怀着极大的兴趣阅读了Kamintsky等人的文章.该研究使用动态增强MRI来计算神经精神系统性红斑狼疮（NPSLE）患者的血脑屏障（BBB）渗漏率。本文报道了SLE患者血脑屏障渗漏率高于对照组。几乎四分之一的SLE患者表现出广泛的血脑屏障渗漏，这组SLE患者的大脑灰质体积较小，整体认知功能受损。本研究为NPSLE患者血脑屏障受损提供了客观证据。然而，导致NPSLE中BBB渗漏的确切机制仍然难以捉摸。作者提出抗核糖体P和抗NR 2抗体和补体激活产物作为BBB渗漏的可能促成因素的作用。2 3此外，一些非系统性红斑狼疮相关因素，例如吸烟、高血压和全身感染，也会增加血脑屏障的渗透性。4在这里，我们想提到其他潜在的机制来解释NPSLE中较高的BBB泄漏。中枢神经系统（CNS）以前被认为没有经典的淋巴引流系统。5然而，几项使用示踪剂注射到脑脊液（CSF）中的研究显示，淋巴引流从CNS进入颈部淋巴结（CLN）。6 7一项使用动物模型的研究发现了硬脑膜窦内的功能性淋巴管，这些淋巴管与深部CLN相连，能够从CSF中携带液体和免疫细胞。8这些发现挑战了中枢神经系统缺乏淋巴引流系统的概念。免疫细胞可能通过从深层和浅层淋巴系统到达大脑而导致神经炎症。一项研究表明，切除CNS引流淋巴结可减少实验性自身免疫性脑脊髓炎的CNS炎症。9最近一项使用局灶性脑缺血动物模型的研究显示，缺血性中风通过血管内皮生长因子（VEGF）-C/VEGF受体（VEGFR）-3信号传导触发CLN中淋巴管内皮的激活，而手术切除浅表CLN可改善中风后炎症并减少脑损伤。这些研究表明，淋巴系统和CLN在CNS炎症中起重要作用。7 9此外，另一项使用高分辨率脑膜光学成像对活斑马鱼进行的研究证实了脑膜淋巴网络从大脑中排出间质液。该研究还表明，中性粒细胞可以很容易地在该淋巴管腔内运输。10在狼疮易感小鼠中的研究（MRL/MpJ-Faslpr/lpr）显示脉络丛中三级淋巴结构形成和淋巴细胞运输到脑中的位点。在人类NPSLE患者的脑组织学分析中显示了通过脉络丛的白细胞迁移增加。11我们认为，中枢神经系统淋巴系统功能失调和通过CLN的免疫细胞运输增加在与NPSLE相关的神经炎症中发挥着重要作用。此外，它可能通过增加NPSLE中促炎细胞因子的产生和补体激活而导致BBB受损。CNS淋巴系统在神经炎症和BBB通透性中的确切作用需要进一步研究，以更好地了解NPSLE的发病机制并找到潜在的治疗靶点。
We read the article by Kamintsky et al 1 with great interest. The study used dynamic contrast-enhanced MRI to calculate cross Blood–brain barrier (BBB) leakage rates in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). This article reported that patients with SLE had higher BBB leakage compared with controls. Almost a quarter of patients with SLE showed extensive BBB leakage and this SLE group had smaller cerebral grey matter volumes and impaired global cognitive function. The study provided objective evidence of impaired BBB in NPSLE. However, the exact mechanisms resulting in BBB leakage in NPSLE remain elusive. The authors have suggested a role of antiribosomal P and anti-NR2 antibodies and complement activation products as possible contributing factors to BBB leakage. 2 3 Also, some non-SLE-related factors, such as smoking, hypertension and systemic infections, can increase BBB permeability. 4 Here, we want to mention other potential mechanisms to explain higher BBB leakage in NPSLE. The central nervous system (CNS) was previously considered to not have a classical lymphatic drainage system. 5 However, several studies using tracers injected into cerebrospinal fluid (CSF) revealed lymphatic drainage from CNS into cervical lymph nodes (CLNs). 6 7 A study using animal models discovered functional lymphatic vessels lining dural sinuses which are connected to deep CLNs and are able to carry fluid and immune cells from CSF. 8 These discoveries challenged the concept of lack of lymphatic drainage system in the CNS. The immune cells may contribute to neuroinflammation by reaching the brain via lymphatics from deep and superficial lymphatic systems. One study showed that excision of the CNS-draining lymph nodes reduced the CNS inflammation in experimental autoimmune encephalomyelitis. 9 A recent study using animal models of focal cerebral ischemia revealed that ischaemic stroke triggered activation of lymphatic endothelium in CLNs via vascular endothelial growth factor (VEGF)-C/VEGF receptor (VEGFR)-3 signalling, while surgical excision of superficial CLNs improved poststroke inflammation and reduced brain injury. 7 These studies suggest that the lymphatic systemic and CLNs play an important role in CNS inflammation. 7 9 In addition, another study in living zebrafish using high-resolution optical imaging of the meninges confirmed a meningeal lymphatic network draining interstitial fluid from the brain. The study also showed that neutrophils could be readily trafficking within this lymphatic vessel lumen. 10 Studies in lupus prone mice (MRL/MpJ-Faslpr/lpr) showed tertiary lymphoid structure formation in the choroid plexus and a site for lymphocyte trafficking into the brain. Increased leucocyte migration via choroid plexus was shown in histological analysis of brain in human NPSLE patients. 11 We suggest that a dysfunctional CNS lymphatic system and increased immune cell trafficking via CLNs play an important role in the neuroinflammation associated with NPSLE. In addition, it may contribute to impaired BBB by increased production of pro-inflammatory cytokines and complement activation in NPSLE. The exact role of the CNS lymphatic system in neuroinflammation and BBB permeability requires further research to better understand the pathogenesis of NPSLE and finding a potential therapeutic target.