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.
Highlights
Neurotropic viral infections pose a major challenge when considering immune modulatory treatment for patients with autoimmune diseases
One of the most devastating of these consequences is progressive multi-focal leukoencephalopathy (PML), a rare demyelinating disease caused by opportunistic infection of the central nervous system (CNS) by JC polyomavirus (JCV; human polyomavirus 2) [1, 2]
Lipid-specific IgM provides protection against neurotropic viruses in an IFNAR1 -dependent manner To test the hypothesis that lipid-specific IgMs induce a functional anti-viral response in the CNS, we examined the anti-viral properties of the murine IgM monoclonal antibody O4, recognising sulfatide (3-O-sulfogalactosylceramide), a major target of the intrathecal antibody response in multiple sclerosis (MS) [20]
Summary
Neurotropic viral infections pose a major challenge when considering immune modulatory treatment for patients with autoimmune diseases. Immune-suppressed individuals are at an increased risk of developing PML [5]. This has important implications for the clinical management of primary and secondary immune deficiencies, as well as autoimmune diseases in which immunosuppression is a primary treatment option [4]. The latter include multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS [6], in which PML can develop in association with immunomodulatory disease modifying therapies including natalizumab [7] and fumaric acid esters [8]
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