Department of Neurology with Institute of Translational Neurology, University Hospital Münster, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan - BP 3028 - 31024, Toulouse Cedex 3, Toulouse, France.
Nat Commun. 2019 Dec 18;10(1):5779. doi: 10.1038/s41467-019-13593-5.
Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
神经炎症通常与血脑屏障功能障碍有关，后者导致神经组织损伤。在这里，我们揭示了 Susac 综合征 (SuS) 的病理生理学，这是一种具有中枢神经系统 (CNS) 血管内皮病的神秘神经炎症性疾病。通过研究 SuS 患者的血液、脑脊液和中枢神经系统中的免疫细胞，我们发现终末分化的激活细胞毒性 CD8 T 细胞 (CTL) 的寡克隆扩增。源自 SuS 患者和新开发的模拟该疾病的转基因小鼠模型的神经病理学数据表明，CTL 附着在 CNS 微血管的不同区域，并极化颗粒酶 B，这很可能导致观察到的内皮细胞损伤和微出血。通过抗 α4 整合素干预阻断 T 细胞黏附可改善临床前模型中的疾病。同样，接受那他珠单抗和其他治疗的四名 SuS 患者的疾病严重程度降低。我们的研究确定了 CD8 T 细胞介导的内皮病变是 SuS 的关键疾病机制，并突出了治疗机会。
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