Virus-Specific Antibody, in the Absence of T Cells, Mediates Demyelination in Mice Infected with a Neurotropic Coronavirus

Abstract

The human disease multiple sclerosis (MS) is an immunemediated, chronic inflammatory disease manifested clinically by neurological deficits and histologically by multiple foci of demyelination. T cells are detected in active demyelinating lesions and a critical role for these cells in demyelination has been clearly demonstrated in several animal models of demyelination, including rodents with experimental autoimmune encephalitis (EAE) and mice infected with coronaviruses or Theiler's murine encephalomyelitis virus. [1][2][3] Mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHM) develop acute and chronic demyelinating diseases. We and others 4 -6 have shown that demyelination was not detected in JHM-infected mice lacking T and B cells [either mice with severe combined immunodeficiency or mice lacking functional recombination activating enzyme 1 (RAG1 Ϫ/Ϫ )]. However, adoptive transfer of syngeneic splenocytes from JHM-immune mice resulted in rapid and reproducible demyelination. 6,7 Depletion of T cells abrogated demyelination showing that T cells were necessary and B or other splenic cells were not sufficient for demyelination to occur. Either CD8 or CD4 T cells, in the absence of the other subset, were able to mediate demyelination in this model. 4 In these experiments, T cells were transferred into RAG1 Ϫ/Ϫ mice 4 days after they were immunized with JHM. The innate immune system was activated by JHM infection before Tcell transfer, as shown by up-regulated expression of several proinflammatory cytokines and chemokines, such as tumor necrosis factor-␣, MIP-2, CCL7 (MCP-3), CCL4 (MIP-1␤), CCL2 (MCP-1), CXCR10 (IP-10), and CCL5 (RANTES) in the central nervous system (CNS). 8 This intense inflammatory milieu is likely critical for the rapid recruitment and activation of T cells to the CNS after adoptive transfer.Less is known about the role of humoral immune factors in MS, but several features suggest that B cells or antibodies are involved in myelin destruction. 9 Oligoclonal expansion of B cells is observed in the cerebrospinal fluid of patients with MS. Also, high levels of immunoglobulin are detected in the cerebrospinal fluid. 10 Some of these cerebrospinal fluid-derived antibodies are directed against myelin proteins and pathogens such as Epstein-Barr virus 11 and varicella-zoster virus.

Immunopathogenesis of coronavirus infections: implications for SARS

“…Although the antiviral T-cell response is crucial for MHV-JHM-or MHV-A59-induced demyelination in normal mice, MHV-JHM-specific antibodies (in the absence of any transferred T cells) can mediate demyelination in infected Rag1 -/mice 75 . Virus-specific T cells and antibodies activate macrophages and/or microglia, resulting in their migration into the white matter of the CNS and, subsequently, in demyelination.…”

Neurotropic Coronavirus Infections

“…As discussed above, passive administration of antivirus antibody also results in demyelinating disease in 2.2-V-1-infected RAG1 −/− mice. Antibody-mediated demyelination is dependent upon both complement and Fcγ-activating receptors since demyelination occurs to a much lesser extent in FcRγ −/− mice and after depletion of complement with cobra venom factor (Kim and Perlman 2005b ).…”

Infections and multiple sclerosis

“…However, in studies of remyelination it was noted that new areas of subclinical demyelination appeared to be developing concurrently with remyelination of older lesions (Herndon et al, 1975(Herndon et al, , 1977. The pathogenesis appears to be complex, with studies showing that late demyelination does not occur in mice lacking B or T cells, but does occur with transfer of virus-specific T cells or virus-specific antibodies (Stohlman and Hinton, 2001;Kim and Perlman, 2005). In addition, both monocyte-derived macrophages and microglia are present in regions of demyelination and can be observed to contact demyelinating axons (Templeton et al, 2008;Bender and Weiss, 2010).…”