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

Autor: Marieke Pingen, Katie J. Chapple, Tiia Semenoff, Clive S. McKimmie, Lorna Hayden, Christopher Linington, Arthur E. Warrington, Xiaohong Shi, Julia M. Edgar, Verena Schultz, Moses Rodriguez, Katja Thümmler, Simon F. Merz
Rok vydání: 2020
Předmět:
0301 basic medicine
Nervous system
Multiple Sclerosis
IgM
viruses
Central nervous system
Autoantigens
lcsh:RC346-429
Pathology and Forensic Medicine
Rats
Sprague-Dawley
Leukoencephalopathy
Immunocompromised Host
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Natalizumab
Immune system
medicine
Animals
Humans
Immunologic Factors
lcsh:Neurology. Diseases of the nervous system
Autoantibodies
business.industry
Research
Progressive multifocal leukoencephalopathy
Multiple sclerosis
Viral encephalitis
Leukoencephalopathy
Progressive Multifocal
Type-I interferon
Interferon stimulated genes
medicine.disease
Lipids
Rats
Mice
Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Immunoglobulin M
John Cunningham polyomavirus (JCV)
Immunology
Microglia
Neurology (clinical)
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-16 (2020)
Acta Neuropathologica Communications
ISSN: 2051-5960
DOI: 10.1186/s40478-020-01011-7
Popis: 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.
Databáze: OpenAIRE
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