T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease.
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 B cell-deficient mice failed to contain MHV CNS infection and developed progressive demyelinating disease, germline IgM produced in activation-induced cytidine deaminase-deficient 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 B 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.
Institute of Immunobiology, Kantonal Hospital St Gallen, St Gallen CH-9007, Switzerland.
Cristina
C
Gil-Cruz
Christian
C
Perez-Shibayama
Sonja
S
Firner
Ari
A
Waisman
Ingo
I
Bechmann
Volker
V
Thiel
Luisa
L
Cervantes-Barragan
Burkhard
B
Ludewig
D000704:Analysis of Variance; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology / Q000821:virology*; D003564:Cytidine Deaminase / Q000172:deficiency; D003711:Demyelinating Diseases / Q000276:immunology / Q000821:virology*; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019013:CD40 Antigens; D007075:Immunoglobulin M; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase