Antibody-secreting cells in the central nervous system in an animal model of MS: Phenotype, association with disability, and in vitro production of antibody

Abstract

Little is known about antibody production within the central nervous system, called intrathecal antibody production (ITAbP). Mice infected with Theiler's murine encephalomyocarditis virus (TMEV) develop an immune-mediated demyelinating disease(TMEV-IDD), characterized by progressive weakness associated with robust ITAbP, CNS inflammation and demyelination. TMEV-IDD represents an excellent model of human multiple sclerosis (MS), especially its progressive disability. The mechanism of the weakness in this disease is unknown but there is considerable evidence that it is immune-mediated. Our hypothesis was that the disability in the model is induced by robust ITAbP by antibody-secreting cells(ASCs) in the CNS. We further hypothesized that these ASCs are predominantly CD138+ plasma cells, driven by the persistence of virus at high levels in the central nervous system (CNS) as well as high levels of B-cell activating factor (BAFF). In order to test these hypotheses we infected mice with TMEV, and correlated measures of ITAbP with disability. Measures of ITAbP were ELISpot and IgG gene expression, while disability was tested by Rotarod. We found that disability was highly correlated with ITAbP, assayed by number of CNS ASCs as well as amount of IgG mRNA. CNS ASCs were primarily CD138+, and produced high levels of IgG enriched for reactivity to TMEV. There were high levels of BAFF production in the CNS, but these levels were only minimally higher in infected mice than in uninfected controls. TMEV and IgG RNA were distributed throughout the spinal cord. These data are the first demonstrating that ITAbP is highly correlated with disability in TMEV infection, an excellent model of human MS. Our data raise the possibility that ITAbP contributes significantly to disability, both in this model and in MS.