Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors.
Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors.
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DOI：
10.1084/jem.20180776
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Diamond B
中科院分区：
文献类型：
--
作者：
Nestor J;Arinuma Y;Huerta TS;Kowal C;Nasiri E;Kello N;Fujieda Y;Bialas A;Hammond T;Sriram U;Stevens B;Huerta PT;Volpe BT;Diamond B
内斯特等人。检查进入大脑的狼疮抗体如何导致神经元功能障碍和认知障碍。结果表明，激活的小胶质细胞对于神经元损伤至关重要，抑制它们可以保护神经元功能和认知。 40-90% 的系统性红斑狼疮 (SLE) 患者会出现认知障碍，其特点是产生针对核抗原（尤其是 DNA）的自身抗体。我们发现抗 DNA 抗体的一个子集（称为 DNRAb）与 N-甲基-d-天冬氨酸受体 (NMDAR) 发生交叉反应并增强 NMDAR 信号传导。在患者中，DNRAb 的存在与空间记忆障碍有关。在小鼠模型中，DNRAb 介导的大脑病理学经历了兴奋性毒性神经元丧失的急性期，随后是神经元完整性的持续改变和空间记忆障碍。只有在大脑中不再检测到 DNRAb 后，后一种病理学才会变得明显。在这里，我们研究短暂暴露于抗体介导的长期神经元功能障碍的机制。我们发现激活的小胶质细胞和 C1q 是神经元损伤的关键介质。我们进一步表明，血管紧张素转换酶（ACE）的中枢作用抑制剂可以防止小胶质细胞活化并保护神经元功能和认知表现。因此，ACE 抑制是旨在减轻认知功能障碍的临床试验的有力候选者。
Nestor et al. examine how lupus antibodies that enter the brain cause neuronal dysfunction and cognitive impairment. The results show that activated microglia are critical for neuronal damage and that inhibiting them can preserve neuronal function and cognition. Cognitive impairment occurs in 40–90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.
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影响因子：
4.6
作者：
Acharya MM;Green KN;Allen BD;Najafi AR;Syage A;Minasyan H;Le MT;Kawashita T;Giedzinski E;Parihar VK;West BL;Baulch JE;Limoli CL
通讯作者：
Limoli CL
HMGB1：内源性危险信号。
影响因子：
5.7
作者：
Klune, John R.;Dhupar, Rajeev;Cardinal, Jon;Billiar, Timothy R.;Tsung, Allan
通讯作者：
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由自身抗体引起的N-甲基-D-天冬氨酸受体引起的空间认知的选择性损害。
影响因子：
11.1
作者：
Chang EH;Volpe BT;Mackay M;Aranow C;Watson P;Kowal C;Storbeck J;Mattis P;Berlin R;Chen H;Mader S;Huerta TS;Huerta PT;Diamond B
通讯作者：
Diamond B
影响因子：
9.3
作者：
Feldman P;Due MR;Ripsch MS;Khanna R;White FA
通讯作者：
White FA
影响因子：
10.6
作者：
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通讯作者：
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