H-2 Genes in TMEV-Induced Demyelination, A Model for Multiple Sclerosis
Theiler’s murine encephalomyelitis virus (TMEV) is a natural enteric pathogen of mice which, upon entry into the CNS, sets up a persistent infection that, in some strains of mice, results in an immunologically-mediated, progressive chronic demyelinating disease with histopathological and clinical similarities to human multiple sclerosis. Although the CNS virus infection persists in all strains, only some go on to develop the demyelinating disease. This susceptibility has a strong genetic basis which involves both H-2 and non-H-2 loci. Comparisons involving different combinations of susceptible and resistant strains indicate the involvement of numerous loci, not all of which are apparent in any given comparison. The differences between the susceptible DBA/2J and resistant C57BL/6 and C57BL/10 strains are primarily dependent upon H-2 genotype and at least one non-H-2 gene, with resistance being dominant to susceptibility. The D region of H-2 has a strong influence (H-2 b associated with resistance and H-2 d with susceptibility) and substitution, in appropriate hybrids, of single gene mutations of the H-2D b gene abrogates resistance. This may mean that resistance is, in fact, an active process mediated, for example, by specific suppression.
In DBA/2, the H-2 d haplotype is associated with susceptibility, unlike the H-2 identical, but resistant, BALB/c strain. The resistance associated with H-2 b is not absolute and can, in segregating populations be overcome by the non-H-2 genome. It is likely that critical combinations of genes, e.g. those encoding H-2 and the T cell receptor chains, are the determining factors in disease susceptibility or resistance.
KeywordsMultiple Sclerosis Demyelinating Disease Susceptible Strain Mononuclear Cell Infiltration Single Gene Mutation
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- Clatch, R.J., Melvold, R.W., Dal Canto, M.C., Miller, S.D. and Lipton, H.L., 1987, The Theiler’s murine encephalomyelitis virus (TMEV) model for multiple sclerosis shows a strong influence of the murine equivalents of HLA-A, -B and -C, J. Neuroimmunol.: (in press).Google Scholar
- Dal Canto, M.C. and Lipton, H.L., 1976, Primary demyelination in Theiler’s virus infection, Lab. Invest. 33: 626.Google Scholar
- Lipton, H.L., Miller, S., Melvold, R., and Fujinami, R.S.,1986, Theiler’s murine encephalomyelitis virus (TMEV) infection in mice as a model for multiple sclerosis, in: “Concepts in Viral Pathogenesis II”, A.L. Notkins and M.B.A. Oldstone, eds., Springer-Verlag, New York.Google Scholar
- Melvold, R.W. Jokinen, D.M., Knobler, R.L. and Lipton, H.L., 1987, Variations in genetic control of susceptibility to Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Differences between susceptible SJL/J and resistant BALB/c strains map near the T cell B-chain constant gene on chromosome 6, J. Immunol. 138: 1429.PubMedGoogle Scholar
- Nathanson, N. and Miller, A., 1978, Epidemiology of multiple sclerosis: critique of evidence for a viral etiology, Am. J. Epidem. 107: 451.Google Scholar