Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus

Mice infected with mouse hepatitis virus strain JHM (MHV-JHM) develop a chr onic demyelinating encephalomyelitis that is in large part immune mediated. Potential mechanisms of immune activity were assessed using an adoptive tr ansfer system. Mice deficient in recombinase-activating gene function (RAG1 (-/-)), defective in B- and T-cell maturation, become persistently infected with MHV but do not develop demyelination. Adoptive transfer of splenocyte s from mice immunized to MHV into RAG1(-/-) mice infected with an attenuate d strain of the virus results in the rapid and progressive development of d emyelination. Most striking, adoptive transfer resulted, within 5 to 6 days , in extensive recruitment of activated macrophages/microglia to sites of d emyelination within the spinal cord. Clearance of virus antigen occurred pr eferentially from the gray matter of the spinal cord. Apoptotic cells were identified in both the gray and white matter of the central nervous system (CNS) from RAG1(-/-) mice before and after adoptive transfer, with a modera te increase in number, but not distribution, of apoptotic cells following t he development of demyelination. These results suggest that apoptosis follo wing MHV-JHM infection of the murine CNS is not sufficient to cause demyeli nation. These results, showing that macrophage recruitment and myelin destr uction occur rapidly after immune reconstitution of RAG(-/-) mice, suggest that this will be a useful system for investigating MHV-induced demyelinati on.