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Background: The epidemiology of multiple sclerosis (MS) suggests that environmental factors such as infections with coronaviruses critically determine the risk for this chronic demyelinating disease. Infection of the CNS with neurotropic mouse coronavirus (MHV) provides a unique model situation that reproduces the important pathological aspects of MS-like neurodegenerative disease: chronic immune activation in peripheral lymphoid organs, persistent inflammatory responses with activation/destruction of glia cells, demyelination, and axonal death. Thus, studying this mouse model can provide a better understanding of the basic mechanisms underlying acute virus-induced CNS pathologies and those factors that critically impinge on chronic demyelination. In a series of preliminary experiments, we have assessed the impact of antibodies in the course of MHV-induced demyelinating disease using B cell-deficient JHT mice, and activation-induced cytidine deaminase (AID)-deficient mice which cannot perform class-switch recombination and somatic hypermutation. Our data show that CNS infection with MHV in JHT mice leads to chronic paralyzing disease. Importantly, IgM antibodies present in AID-deficient mice were sufficient to block development of chronic inflammatory CNS disease.
Working hypothesis: In this project, we will work along the major hypothesis that the presence of B cells secreting unmutated antiviral IgM antibodies in the CNS is necessary and sufficient to attenuate virus-mediated CNS inflammation and hence to prevent chronic demyelinating disease.
Specific aims: Since persisting virus represents the major driver for chronic immune activation in the CNS, we will first determine which CNS cells provide the optimal survival niche for the persisting virus. To this end, enhanced green fluorescent protein (EGFP)- and Cre recombinase-recombinant MHV mutants will be employed. Second, we will determine the B cell subsets (B-1a, B-1b, or B2) producing CNS-protective IgM. Here, we will use adoptive transfer of sorted B cell subsets (naïve or MHV immune) into JHT mice and generation of bone marrow-chimeric mice in order to reconstitute the immune system with defined B cell populations. The third aim comprises the mechanistic dissection of IgM-mediated protection using infection of complement-deficient mice, and adoptive transfer of chemokine receptor-deficient B cells into JHT mice. Finally, we plan to assess the contribution of IgG to the efficient clearing of the virus both in the initial phase of virus-induced encephalomyelitis and in the chronic phase of demyelinating disease.
Potential significance: The work on the basic mechanisms of antibody-mediated protection from chronic inflammatory CNS disease will deliver critical new knowledge on the pathogenesis of infection-associated demyelinating disease. The combination of recombinant virus mutants with particular transgenic mouse models will provide novel insights on the immunopathological mechanisms of MS-like demyelinating diseases.