Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10

Olga L Rojas; Anne-Katrin Pröbstel; Elisa A Porfilio; Angela A Wang; Marc Charabati; Tian Sun; Dennis S W Lee; Georgina Galicia; Valeria Ramaglia; Lesley A Ward; Leslie Y T Leung; Ghazal Najafi; Khashayar Khaleghi; Beatriz Garcillán; Angela Li; Rickvinder Besla; Ikbel Naouar; Eric Y Cao; Pailin Chiaranunt; Kyle Burrows; Hannah G Robinson; Jessica R Allanach; Jennifer Yam; Helen Luck; Daniel J Campbell; David Allman; David G Brooks; Michio Tomura; Ryan Baumann; Scott S Zamvil; Amit Bar-Or; Marc S Horwitz; Daniel A Winer; Arthur Mortha; Fabienne Mackay; Alexandre Prat; Lisa C Osborne; Clinton Robbins; Sergio E Baranzini; Jennifer L Gommerman

doi:10.1016/j.cell.2018.11.035

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10

Cell. 2019 Jan 24;176(3):610-624.e18. doi: 10.1016/j.cell.2018.11.035. Epub 2019 Jan 3.

Authors

Olga L Rojas¹, Anne-Katrin Pröbstel², Elisa A Porfilio¹, Angela A Wang¹, Marc Charabati³, Tian Sun¹, Dennis S W Lee¹, Georgina Galicia¹, Valeria Ramaglia¹, Lesley A Ward¹, Leslie Y T Leung¹, Ghazal Najafi¹, Khashayar Khaleghi¹, Beatriz Garcillán⁴, Angela Li⁵, Rickvinder Besla⁶, Ikbel Naouar¹, Eric Y Cao¹, Pailin Chiaranunt¹, Kyle Burrows¹, Hannah G Robinson⁷, Jessica R Allanach⁷, Jennifer Yam¹, Helen Luck⁵, Daniel J Campbell⁸, David Allman⁹, David G Brooks¹⁰, Michio Tomura¹¹, Ryan Baumann², Scott S Zamvil¹², Amit Bar-Or¹³, Marc S Horwitz¹⁴, Daniel A Winer⁶, Arthur Mortha¹, Fabienne Mackay⁴, Alexandre Prat³, Lisa C Osborne⁷, Clinton Robbins¹⁵, Sergio E Baranzini¹⁶, Jennifer L Gommerman¹⁷

Affiliations

¹ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Neuroimmunology Unit, CRCHUM and Department of Neurosciences, Faculty of Medicine, Université de Montréal, QC H2X 0A9, Canada.
⁴ University of Melbourne, School of Biomedical Sciences, Parkville, VIC 3010, Australia.
⁵ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
⁶ Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory and Medicine Pathology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁷ Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
⁸ Benaroya Research Institute and Department of Immunology University of Washington School of Medicine, Seattle, WA 98101, USA.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada.
¹¹ Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka Prefecture 584-8540, Japan.
¹² Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Program in Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Department of Laboratory and Medicine Pathology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁵ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory and Medicine Pathology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁶ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Graduate Program in Bioinformatics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁷ Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jen.gommerman@utoronto.ca.

Abstract

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA⁺ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA⁺ PC. Furthermore, mice with an over-abundance of IgA⁺ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA⁺ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

Keywords: B cells; EAE; IgA; MS; experimental autoimmune encephalomyelitis; microbiota; multiple sclerosis; plasma cells; small intestinal lamina propria.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Encephalomyelitis, Autoimmune, Experimental / immunology
Humans
Immunoglobulin A / immunology
Immunoglobulin A / metabolism*
Interleukin-10 / metabolism*
Intestinal Mucosa / metabolism
Intestines / immunology*
Mice
Mice, Inbred C57BL
Multiple Sclerosis / immunology
Neuroimmunomodulation / immunology
Plasma Cells / metabolism

Substances

Immunoglobulin A
Interleukin-10

Abstract

Publication types

MeSH terms

Substances

Grants and funding