Lipid-specific IgM antibodies in multiple sclerosis and viral immunity

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and the leading cause of disability in young adults. Over the last 20 years, a plethora of drugs have been approved for the treatment of MS, many of which target the immune response to reduce CNS inflammation. Although effective, many of these therapies have been associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), a fatal infection of the CNS by the John Cunningham virus. As a result, these effective therapeutics are used with caution pending the establishment of reliable risk stratification tools. A recent association between intrathecal lipid-reactive IgM synthesis and reduced incidence of PML in natalizumab-treated MS prompted our investigation into the antiviral properties of lipid-reactive IgM antibodies. Using murine heterogenous CNS cultures, we investigated the antiviral properties of both human and mouse IgMs. Initial investigations focused on the sulfatide-reactive IgM O4, a major target of the IgM response in MS patients. Using microarray analysis, RT-qPCR, and fluorescence in situ hybridisation, alongside genetic knock-out cultures and a range of pharmacological inhibitors, it was deduced that O4 could stimulate microglia to upregulate interferon beta (IFN-β) in a cGAS-STING-dependent manner, triggering global interferon stimulated gene (ISG) expression in major cell-types of the CNS. This interferon (IFN) response limited the replication of two genetically unrelated viruses, with final experiments focused on developing an in vivo model to investigate these antiviral IgMs. The data presented in this thesis provide a plausible explanation for the association between intrathecal IgM synthesis and reduced incidence of PML in natalizumab-treated MS patients. This research will aid risk stratification of MS patients, allowing safe access to effective therapeutics. Further understanding of the mechanism of this antibody-mediated response could lead to the development of an antiviral therapy for use as a co-treatment in MS or as a broad-spectrum therapeutic for the treatment of viral encephalitis.