Gut-educated IgA plasma cells defend the meningeal venous sinuses.
Fitzpatrick Z., Frazer G., Ferro A., Clare S., Bouladoux N., Ferdinand J., Tuong ZK., Negro-Demontel ML., Kumar N., Suchanek O., Tajsic T., Harcourt K., Scott K., Bashford-Rogers R., Helmy A., Reich DS., Belkaid Y., Lawley TD., McGavern DB., Clatworthy MR.
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<sup>1</sup>. 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<sup>2</sup>. 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<sup>+</sup> 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.