Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

Hayden, L. et al. (2020) Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis. Acta Neuropathologica Communications, 8, 135. (doi: 10.1186/s40478-020-01011-7) (PMID:32792006) (PMCID:PMC7427287)

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Abstract

Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Muecklisch, Dr Katja and Schultz, Dr Verena and Chapple, Dr Katie and Shi, Dr Xiaohong and SEMENOFF, Tiia and Linington, Professor Christopher and Edgar, Professor Julia and Hayden, Lorna and Pingen, Dr Marieke and McKimmie, Dr Clive
Authors: Hayden, L., Semenoff, T., Schultz, V., Merz, S. F., Chapple, K. J., Rodriguez, M., Warrington, A. E., Shi, X., McKimmie, C. S., Edgar, J. M., Thümmler, K., Linington, C., and Pingen, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Acta Neuropathologica Communications
Publisher:BioMed Central
ISSN:2051-5960
ISSN (Online):2051-5960
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Acta Neuropathologica Communications 8:135
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173756From diagnosis to function: the pathophysiological significance of intra-thecal antibody responses to lipids in multiple sclerosis.Julia EdgarMedical Research Scotland (MEDRESSC)PhD-1031-2016III - Immunology
164936Chemokine-mediated innate immune responses to arthropod bites and their virusesClive McKimmieMedical Research Council (MRC)G1001724III - Immunology
305019Enhancing innate anti-viral immunity in the nervous system: a generalised strategy to treat viral encephalitisMarieke PingenGlasgow Children`s Hospital Charity (GCHC)GCHC/PSG/2018/01III - Immunology