Gut-educated IgA plasma cells defend the meningeal venous sinuses

Zachary Fitzpatrick, Gordon Frazer, Ashley Ferro, Simon Clare, Nicolas Bouladoux, John Ferdinand, Zewen Kelvin Tuong, Maria Luciana Negro-Demontel, Nitin Kumar, Ondrej Suchanek, Tamara Tajsic, Katherine Harcourt, Kirsten Scott, Rachel Bashford-Rogers, Adel Helmy, Daniel S. Reich, Yasmine Belkaid, Trevor D. Lawley, Dorian B. McGavern () and Menna R. Clatworthy ()
Additional contact information
Zachary Fitzpatrick: University of Cambridge
Gordon Frazer: University of Cambridge
Ashley Ferro: University of Cambridge
Simon Clare: Wellcome Sanger Institute
Nicolas Bouladoux: National Institutes of Health
John Ferdinand: University of Cambridge
Zewen Kelvin Tuong: University of Cambridge
Maria Luciana Negro-Demontel: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Nitin Kumar: Wellcome Sanger Institute
Ondrej Suchanek: University of Cambridge
Tamara Tajsic: University of Cambridge
Katherine Harcourt: Wellcome Sanger Institute
Kirsten Scott: University of Cambridge
Rachel Bashford-Rogers: University of Oxford
Adel Helmy: University of Cambridge
Daniel S. Reich: National Institutes of Health
Yasmine Belkaid: National Institutes of Health
Trevor D. Lawley: Wellcome Sanger Institute
Dorian B. McGavern: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Menna R. Clatworthy: University of Cambridge

Nature, 2020, vol. 587, issue 7834, 472-476

Abstract: Abstract 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 cells1. 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 brain2. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2886-4

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