8 April 2002 18:00 GMT
by Martina Habeck, BioMedNet News
Studying viral infection in the nervous system of mice has led US neuropharmacologist Michael Buchmeier towards an explanation for the very different inflammatory responses underlying multiple sclerosis (MS) and acute encephalitis.
Researchers have several animal models to investigate the immunopathological events that result in MS. One of these is a mouse infected with mouse hepatitis virus (MHV), an RNA virus belonging to the family of Coronaviridae that infects nervous tissue. Although no single viral etiology has been proven for MS, the murine MHV model is valued because the infection causes an immune response similar to that seen in MS: mononuclear cell infiltration and massive destruction of white matter.
In order to evaluate the contribution of the virally induced immune response to the observed symptoms in this model, Buchmeier, professor of neuropharmacology at the Scripps Research Institute in California, infected mice with one of two different MHV strains. One strain, MHV-A59, is known to cause a relatively benign form of the disease, whereas the other, MHV-JHM (also known as MHV-4), results in lethal encephalitis.
Buchmeier examined the immune responses evoked by these two viruses, and found that MHV-JHM infection resulted in a strong and ongoing transcription of interferon beta (IFN-beta), interleukin 6 (IL-6) and IL-1, which are typical mediators of an innate immune response. Macrophage and neutrophil levels were also markedly increased in mice infected with MHV-JHM, compared with MHV-A59 infection, another sign of an innate immune response.
By contrast, MHV-A59 infection triggered a protective adaptive immune response, characterized by an early and sustained accumulation of IFN-gamma RNA and an infiltration of CD8+ T-cells, indicative of an adaptive immune response.
The findings impress John Fazakerley, reader in virology at the University of Edinburgh, who chaired today's session in which Buchmeier presented his data to the Society for General Microbiology at the University of Warwick. Fazakerley was surprised by the dramatic differences in immune response revealed by Buchmeier. Given the complexity of the immune system, he suggests, such a clear-cut separation between innate and adaptive immune responses would not have been expected.
Buchmeier says the findings suggest that in mice infected with MHV-JHM, there is no adequate transition from the innate to the adaptive immune response. Insufficient recruitment of virus-specific T-cells results in an uncontrolled infection, which eventually kills the animal.
"The findings really mean that the fate of the infection is defined very early, this probably applies equally to encephalitis and MS," Buchmeier told BioMedNet News. "The nature of the chronic inflammatory response in the brain is very important."
Buchmeier is now investigating the immune response underlying the mechanism of dymyelination, which is central to MS pathogenesis. "Again, it requires chronic activation of T-cell pathways and macrophages," he said.
Immunotherapy of multiple sclerosis: The end of the beginning
Current Opinion in Immunology, 2001, 13:5:597-600
Jodie Haring, Stanley Perlman
Current Opinion in Microbiology, 2001, 4:4:462-466
Michael J Buchmeier, Thomas E Lane
Current Opinion in Microbiology, 1999, 2:398-402
cells and antibodies in CNS demyelinating disease
Anne H. Cross, John L. Trotter, Jeri-Anne Lyons
Journal of Neuroimmunology, 2001, 112:1-2:1-14
© Elsevier Science Limited 2002