Myelin breakdown in multiple sclerosis (MS) is mediated by me helper T Iymphocyte (T cell) Th1 subset by a process analogous with that of the animal model, experimental autoimmune encephalomyelitis (EAE). Extensive efforts have failed to show dear differences in T cell reactivity to candidate autoantigen peptides of myelin basic protein (MBP) and proteolipid protein (PLP) in individuals with MS compared to healthy controls. This suggests that a different pathogenetic mechanism may be operative. Considerable circumstantial evidence supports a role for a viral infection in MS, although an MS-specific virus has not been identified. Thus, the immunopathologic changes could be caused by a persistent central nervous system (CNS) viral infection with the immune response directed at viral rather than self proteins, but still mediated by the helper T Iymphocyte (T cell) Th1 subset as in EAE. The hypothesis is that a novel virus persists in the CNS to to drive the MS immunopathology. The putative virus replicates continuously in the CNS, driving continuous disease activity that underlies relapsing-remitting MS Viral replication may be similar to that in Theiler's murine encephalomyelitis virus (TME /) infection in mice or Visna virus infection in Icelandic sheep, relevant experimental viral models of MS. Since the putative MS virus may be noncultivatable, transmission attempts to animals and molecular approaches provide the best means of its detection. Two previous attempts to transmit MS to non-human primates in the 1960s to 1970s were not optimal by current standards, and therefore should not dissuade current attempts. This proposal stands in contrast to studies focused on incriminating a specific known pathogen as a cause of MS. We propose to transmit MS to non-human primates by inoculating pairs of 0.5-1.0 year-old chimpanzees and squirrel monkeys intracerebrally (ic) with MS CSF mononuclear inflammatory cells (24 hr collection) and also with acute post-mortem plaques if optimum material becomes available. White matter lesions (serial cranial MRls), and CSF pleocytosis (serial cisternal taps) will detect subclinical disease in the animals. Stereotaxic biopsy will confirm the nature of developing lesions and enable serial brain-to-brain passage to demonstrate a replicating agent and its characterization. We also propose to construct and express MS CSF cDNA libraries in gt-11 as another way of detecting such a virus without prior knowledge of its nature.
| Lipton, Howard L; Liang, Zhiguo; Hertzler, Shannon et al. (2007) A specific viral cause of multiple sclerosis: one virus, one disease. Ann Neurol 61:514-23 |
