Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 8, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-020-01011-7
Keywords
Type-I interferon; Interferon stimulated genes; Viral encephalitis; John Cunningham polyomavirus (JCV); Microglia; IgM
Categories
Funding
- Hertie Stiftung
- Naomi Bramson Trust
- MS Society UK
- Medical Research Scotland [PhD-1031-2016]
- Medical Research Council
- Medical Research Council New Investigator Research Grant [G1001724]
- Glasgow Children Hospital Charity Project Support Grant [GCHC/PSG/2018/01]
- MRC [G1001724] Funding Source: UKRI
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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-beta in a cGAS-STING-dependent manner, which induces an IFN-alpha/beta-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.
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