期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13593-5
关键词
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资金
- European Susac Consortium (EuSaC)
- German Research Foundation grant (DFG) [GR3946_3/1]
- Interdisciplinary Center for Clinical Studies (IZKF) [Kl3/010/19]
- IMF grant [KL 111421]
- Collaborative Research Centre [CRC TR128]
- Federal Ministry of Education and Research [FKZ01FI1603A]
- intramural Cell in Motion (CiM) cluster of excellence bridging fund
- Oppenheim Research Grant
- German Research Council through the Munich Cluster for Sastems Neurology [SyNergy EXC 2145, 390857198]
- Inserm
- CNRS
- Toulouse University
- French MS society (ARSEP)
- Foundation pour la Recherche Medicale (FRM)
- French Research Agency (ANR T cell Mig)
- ERA-NET NEURON (Meltra-BBB)
- Institut Universitaire de France
- German Research Foundation (DFG) [SCHW 416/5-2]
- Austrian Science Fund [FWF: P26936-B27, FWF: I3334-B27]
- [SFB1009]
- Austrian Science Fund (FWF) [P26936] Funding Source: Austrian Science Fund (FWF)
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-alpha 4 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.
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