T helper cell-and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (4), p.1233-1238
• Main Authors: Gil-Cruz, Cristina, Perez-Shibayama, Christian, Firner, Sonja, Waisman, Ari, Bechmann, Ingo, Thiel, Volker, Cervantes-Barragan, Luisa, Ludewig, Burkhard
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animal models; Animals; Antibodies; Antibody response; Antimicrobial agents; Antivirals; B lymphocytes; B-Lymphocytes - immunology; Biological Sciences; CD40 Antigens - immunology; Cell activation; Cell adhesion & migration; Cell migration; Central nervous system; Central Nervous System - immunology; Central Nervous System - virology; Central nervous system viral diseases; Chronic infection; Cytidine Deaminase - deficiency; Data processing; Demyelinating diseases; Demyelinating Diseases - immunology; Demyelinating Diseases - virology; Enzyme-Linked Immunospot Assay; Flow Cytometry; Fluorescent Antibody Technique; Helper cells; Immune system; Immunoglobulin G; Immunoglobulin M; Immunoglobulin M - genetics; Immunoglobulin M - immunology; Infections; Inflammatory diseases; Lymph nodes; Lymphocytes B; Lymphocytes T; Mice; Mice, Knockout; Multiple sclerosis; Murine hepatitis virus; Murine hepatitis virus - immunology; Neuroprotection; Niches; Pathogens; Replication; Rodents; T cell receptors; T lymphocytes; T-Lymphocytes, Helper-Inducer - immunology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1115154109

Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody-or cell-deficient mice failed to contain MHV CNS infection and developed progressive demyelinating disease, germline IgM produced in activation-induced cytidine deaminase-def icient mice (aicda⁻⁄⁻) provided long-term protection against the chronic multiple sclerosis-like disease. Furthermore, we found that appropriate B-cell activation within the CNS-draining lymph node and subsequent CXCR3-mediated migration of antiviral IgM-secreting cells to the infected CNS was dependent on CD40-mediated interaction of cells with T helper cells. These data indicate that the CD40-mediated collaboration of T and B cells is critical to secure neuroprotective IgM responses during viral CNS infection.