Gut-educated IgA plasma cells defend the meningeal venous sinuses
Authors: Zachary Fitzpatrick
Ashley Ferro
Nitin Kumar
Adel Helmy
John Ferdinand
Gordon Frazer
Kirsten Scott
Ondrej Suchanek
Trevor D Lawley
Daniel S Reich
Maria Luciana Negro-Demontel
Zewen Kelvin Tuong
Simon Clare
Tamara Tajsic
Nicolas Bouladoux
Dorian B McGavern
Katherine Harcourt
Menna R Clatworthy
Rachel Bashford-Rogers
Yasmine Belkaid
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: central nervous system; meninges; immune cells; IgA-secreting plasma cells; dural venous sinuses
Affiliations: 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., Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK., National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MA, USA., Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK., Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MA, USA., Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MA, USA. ., Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK. ., Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK. ., Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK. .

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. 

Retracted: No

PubPeer comments:
 Dear authors, We have with great interest and excitement discussed your paper u201cGut-educated IgA plasma cells defend the meningeal venous sinusesu201d during our weekly literature meeting. Your results showing the gut-brain connection are intriguing. The discovery of the presence of IgA in the meninges might change the therapeutical approach to some diseases and lead to other findings. Therefore, we look forward to receiving more news from your studies. However, after reading your paper, we were left wondering about a few things that we think would be interesting to see explored or commented on, either here, or in future publications: 1. In fig. 1e you are presenting the mRNA expression of certain immunoglobulins. Have you also measured other isotypes (IgD, IgE, IgM, Ig2a) or were they not present? 2. Why would gut antigens pathogens reach the brain and not, for example, skin antigens pathogens? Are IgA plasmablasts from the airways also homing to the large sinuses in the brain? How do IgA plasma cells know which of them are relevant for brain protection and migrate there? 3. Why should IgA give a better protection against pathogens reaching the brain than other Ig subtypes? Because they are less immunogenic or and less inflammatory? Is pathogen accumulation via antibody opsonization not a bit too risky mechanism for the safety of the brain? The gut has an efficient way of clearing an excessive amount of pathogenic bacteria through diarrhoea. What would happen with an excessive amount of bacteria trapped in the meninges? 4. Does bortezomib treatment affect mice survival? Did you treat the mice with bortezomib alone without C. albicans administration? We would greatly appreciate it if you could share your thoughts on our comments above, as this may aid us (and other readers) in better understanding your work and thus help us all contribute to a fruitful scientific discussion. ,