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

• DOI: 10.1186/s40478-020-01011-7
• Publication Date: 2020-08-13T13:03:48Z
• Authors: Lorna Hayden; Tiia Semenoff; Verena Schultz; Simon F. Merz; Katie J. Chapple; Moses Rodriguez; Arthur E. Warrington; Xiaohong Shi; Clive S. McKimmie; Julia M. Edgar; Katja Thümmler; Chris Linington; Marieke Pingen
• Keywords: 0301 basic medicine; IgM; Multiple Sclerosis; Autoantigens; Rats, Sprague-Dawley; Immunocompromised Host; Mice; 03 medical and health sciences; Animals; Humans; Immunologic Factors; RC346-429; Autoantibodies; Research; Natalizumab; Leukoencephalopathy, Progressive Multifocal; Type-I interferon; Interferon stimulated genes; Viral encephalitis; Lipids; Rats; 3. Good health; Mice, Inbred C57BL; Immunoglobulin M; John Cunningham polyomavirus (JCV); Microglia; Neurology. Diseases of the nervous system

Abstract Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with compromised immune system, such as patients multiple sclerosis (MS) receiving treatment natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS associated markedly lower incidence natalizumab-associated compared to those without this antibody repertoire. Here we demonstrate that subset human and murine IgMs induce functional anti-viral response inhibits replication encephalitic Alpha Orthobunyaviruses multi-cellular central nervous system cultures. These lipid-specific trigger microglia produce IFN-β cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral glia neurons. data identify mediator activity the provide rational explanation why correlates reduced iatrogenic MS.