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. 2005 Mar;166(3):801-9.
doi: 10.1016/S0002-9440(10)62301-2.

Virus-specific antibody, in the absence of T cells, mediates demyelination in mice infected with a neurotropic coronavirus

Taeg S Kim  1 , Stanley Perlman
Affiliations

Virus-specific antibody, in the absence of T cells, mediates demyelination in mice infected with a neurotropic coronavirus

Taeg S Kim et al. Am J Pathol. 2005 Mar.

Abstract

Mice infected with mouse hepatitis virus strain JHM develop an inflammatory demyelinating disease in the central nervous system with many similarities to human multiple sclerosis. The mouse disease is primarily immune-mediated because demyelination is not detected in JHM-infected mice lacking T or B cells but does occur after transfer of JHM-specific T cells. Although less is known about the ability of antibodies to mediate demyelination, the presence of oligoclonally expanded B cells and high concentrations of antibodies (against self or infectious agents) in the central nervous system of many multiple sclerosis patients suggests that antibodies may also contribute to myelin destruction. Here, we show that anti-JHM antibodies, in the absence of T or B cells, caused demyelination in JHM-infected mice. Anti-JHM antibody was detected adjacent to areas of demyelination, consistent with a direct interaction between antibody and infected cells. Demyelination was reduced by 85 to 90% in infected RAG1(-/-) mice lacking normal expression of activating Fc receptors (FcRgamma(-/-)) and by approximately 76% when complement was depleted by treatment with cobra venom factor. These data demonstrate that JHM-specific antibodies are sufficient to cause demyelination and that myelin destruction in the presence of anti-virus antibodies results from a combination of complement- and Fc receptor-dependent mechanisms.

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Figures

Figure 1
Figure 1
Detection of demyelination in anti-JHM antibody-treated mice. JHM-infected RAG1−/− mice received the following treatments at 4 days after infection by intraperitoneal injection: 50 μl (A–C) or 500 μl (G–I) of rabbit anti-JHM sera, 50 μl of rabbit normal sera (D–F), or 5 μg of anti-JHM mAb (5B19.2: J–L). Mice were harvested at 14 to 16 days after infection and serial longitudinal sections (8 μm thick) of spinal cord were examined for demyelination (A, D, G, and J), macrophage/microglia infiltration (B and E), viral antigen (C and F), antibody deposition (H and I), and axons (K and L) as described in Materials and Methods. Demyelination (A) and extensive macrophage/microglia infiltration into the white matter (B) were evident only in mice that received JHM-immune sera, but not in control mice (D and E). However, viral antigen was uniformly distributed throughout spinal cords in both JHM-immune sera-treated (C) and control (F) mice, except in areas of demyelination (C). Antibodies deposited in the CNS (H) were detected exclusively adjacent to areas of frank demyelination. G: An area with a moderate amount of demyelination is depicted in this figure. I: No staining was detected when an irrelevant antibody was used. Axons were preserved (K) in areas of demyelination (J). L: No staining was detected in the absence of SMI312 mAbs. Scale bars: 250 μm (A–I); 125 μm (J–L).
Figure 2
Figure 2
Kinetics of demyelination mediated by either JHM-immune splenocytes (ο, Δ, ▴) or JHM-specific mAb 5B19.2 (♦) in RAG1−/− mice infected with JHM. Demyelination was minimal when JHM-infected RAG1−/− mice were untreated (▿). However, rapid and robust demyelination (15.9 ± 1.9%, n = 7; ο) was observed at 7 days after transfer of JHM-immune splenocytes, as previously described. Demyelination was also detected by 7 days when JHM-immune splenocytes, enriched for either CD4 (10.2 ± 0.6%, n = 9; Δ) or CD8 (15.4 ± 3.2%, n = 7; ▴) T cells were transferred to JHM-infected RAG1−/− mice. Demyelination did not develop as rapidly after treatment with anti-S mAb but reached similar levels by 16 days after infusion (20.5 ± 1.5%, n = 8).
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