Related Experiment Video
Updated: Dec 12, 2025
Author Spotlight: Novel Assay for Studying B-Cell Responses in Multiple Sclerosis Research
Published on: December 1, 2023
Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal
Lorna Hayden1, Tiia Semenoff1, Verena Schultz1
1Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK.
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.
Insights
Certain lipid-reactive IgM antibodies can fight viral infections in the brain. This finding may explain why some multiple sclerosis patients on natalizumab have a lower risk of progressive multifocal leukoencephalopathy.
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a severe brain infection caused by the JC polyomavirus (JCV).
- Patients with compromised immune systems, including those with multiple sclerosis (MS) treated with natalizumab, are at higher risk for PML.
- A lower incidence of natalizumab-associated PML has been observed in MS patients with intrathecal synthesis of lipid-reactive IgM.
Purpose of the Study:
- To investigate the antiviral properties of lipid-reactive IgM.
- To elucidate the mechanism by which lipid-reactive IgM confers protection against viral encephalitis.
- To understand the correlation between lipid-reactive IgM and reduced PML incidence in MS patients.
Main Methods:
- Utilized multi-cellular central nervous system cultures.
- Assessed the effect of lipid-reactive human and murine IgMs on viral replication.
- Investigated the signaling pathways involved, including cGAS-STING and IFN-α/β-receptor 1.
Main Results:
- A subset of lipid-reactive IgMs demonstrated a functional antiviral response, inhibiting Alpha and Orthobunyavirus replication.
- These IgMs activated microglia to produce interferon-beta (IFN-β) via a cGAS-STING-dependent pathway.
- This led to an IFN-α/β-receptor 1-dependent antiviral state in glial cells and neurons.
Conclusions:
- Lipid-reactive IgM mediates antiviral activity within the nervous system.
- The findings provide a mechanistic explanation for the reduced incidence of iatrogenic PML in MS patients with intrathecal lipid-reactive IgM.
- This highlights a potential therapeutic avenue for viral infections in the central nervous system.
