Fitzpatrick Zachary, Frazer Gordon, Ferro Ashley, Clare Simon, Bouladoux Nicolas, Ferdinand John, Tuong Zewen Kelvin, Negro-Demontel Maria Luciana, Kumar Nitin, Suchanek Ondrej, Tajsic Tamara, Harcourt Katherine, Scott Kirsten, Bashford-Rogers Rachel, Helmy Adel, Reich Daniel S, Belkaid Yasmine, Lawley Trevor D, McGavern Dorian B, Clatworthy Menna R
Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MA, USA.
Nature. 2020 Nov;587(7834):472-476. doi: 10.1038/s41586-020-2886-4. Epub 2020 Nov 4.
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.
中枢神经系统在历史上一直被视为免疫豁免部位，但最近的数据表明，脑膜（包围大脑和脊髓的膜）含有多种免疫细胞。到目前为止，研究主要集中在巨噬细胞和T细胞上，但尚未对脑膜体液免疫进行详细分析。在这里，我们表明，在稳态期间，小鼠和人类脑膜含有分泌IgA的浆细胞。这些细胞位于硬脑膜静脉窦附近：血流缓慢且有窗孔的区域，这些窗孔可能使血源性病原体进入大脑。窦周IgA浆细胞随年龄增长以及肠道屏障破坏后而增加。相反，在无菌小鼠中它们很少见，但通过肠道重新定殖可恢复其存在。B细胞受体测序证实脑膜IgA细胞起源于肠道。脑膜浆细胞的特异性耗竭或IgA缺乏导致静脉窦周围区域真菌捕获减少，并在静脉内攻击后增加向大脑的扩散，表明脑膜IgA对于在这个易受攻击的静脉屏障表面保护中枢神经系统至关重要。
