Tröscher Anna R, Klang Andrea, French Maria, Quemada-Garrido Lucía, Kneissl Sibylle Maria, Bien Christian G, Pákozdy Ákos, Bauer Jan
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Department for Pathobiology, Institute of Pathology and Forensic Veterinary Medicine, University of Veterinary Medicine, Vienna, Austria.
Front Immunol. 2017 Oct 18;8:1364. doi: 10.3389/fimmu.2017.01364. eCollection 2017.
Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a feline model of limbic encephalitis with LGI1 antibodies, called feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal model to study pathological mechanisms will, therefore, contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood-brain barrier (BBB) leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdale, and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region-specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by BBB dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that BBB disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points toward another, so far unknown, mechanism of opening the BBB. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.
人类富含亮氨酸的胶质瘤失活蛋白1脑炎（LGI1）是一种自身免疫性边缘叶脑炎，其血清和脑脊液中含有靶向LGI1的抗体，LGI1是电压门控钾通道（VGKC）复合物的一种蛋白质。最近，我们发现一种伴有LGI1抗体的边缘叶脑炎猫模型，称为伴有口面部受累的猫复杂部分性癫痫（FEPSO），与人类LGI1脑炎高度相似。在人类LGI1脑炎中，神经病理学研究很困难，因为可用材料非常少。因此，利用这种天然动物模型来研究病理机制将有助于更好地理解其人类对应疾病。在这里，我们展示了FEPSO的全脑组织病理学分析。我们发现血脑屏障（BBB）渗漏不仅存在于海马体的所有区域，还存在于其他边缘结构，如海马下脚、杏仁核和梨状叶。然而，在其他区域，如小脑，未观察到渗漏。此外，这种脑区特异性免疫球蛋白渗漏与内皮紧密连接的破坏有关。受BBB功能障碍影响的脑区还显示出免疫球蛋白和补体沉积以及神经元细胞死亡。这些神经病理学发现得到了磁共振成像的支持，该成像显示杏仁核和梨状叶的信号和体积增加。重要的是，我们可以证明LGI1脑炎中的BBB紊乱不依赖于全脑存在的T细胞浸润。这一发现指向了另一种迄今未知的打开BBB的机制。免疫球蛋白抗体渗漏到大脑的边缘叶偏好部位可能解释了为什么大多数患有LGI1抗体的患者具有边缘叶表型，尽管靶蛋白LGI1在中枢神经系统中广泛分布。
