Genetic analysis of susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease in the SWR strain.

SWR/J mice are susceptible to immune-mediated central (CNS) demyelination following infection by Theiler's murine encephalomyelitis virus (TMEV). SWR/J susceptibility is genetically dominant, when outcrossed to resistant H-2b strains. Non-H-2 differences between C57BL/6 and C57L/J (both H-2b) alter effects of 'susceptibility' genes, especially H-2q, from SWR/J. Genetic analysis of differential susceptibility to demyelination between SWR/J and C57L/J indicates that one copy of H-2q is sufficient for disease, and that SWR/J mice carry a non-H-2 gene which can lead to disease in the absence of H-2q. Differential susceptibility between SWR/J and C57BL/6 is determined by a single non-H-2 locus, which may or may not be the same as that differing between SWR/J and C57L/J.

T cell receptor expression can switch on and off at a posttranslational level.

The human T acute lymphocytic leukemia cell line, SUP-T13, is a mosaic of TCR/CD3+ and TCR/CD3- cells. Individual SUP-T13 cells can spontaneously switch on and off surface TCR/CD3 expression. This switching was demonstrated by culturing and analysis of single cell clones that were TCR/CD3+ or TCR/CD3-. The rate of switching is about 10(-2)/cell per generation in either direction. This is too high to be due to a spontaneous mutation event. Furthermore, switched cells can revert at similar rates, as demonstrated by repeated cloning and reanalysis. This makes it likely that a regulatory change is responsible for switching. In support of this, all known TCR/CD3 proteins are found intracellularly in TCR/CD3- cells, and they associate with each other as in TCR/CD3+ cells. Furthermore, no structural abnormalities of the TCR/CD3 chains can be seen in TCR/CD3- cells using two-dimensional electrophoresis. However, in these cells, the chains accumulate in great excess intracellularly. This accumulation is specific to the TCR/CD3 complex, as other glycoproteins are still expressed normally on the cell surface. Thus, there is regulation of TCR expression at a posttranslational level. These TCR/CD3- cells may lead to the identification of novel protein(s) involved in glycosylating, processing, or transporting the TCR/CD3 complex. Potential loss of TCR/CD3 expression may also limit the feasibility of TCR-based therapies for T cell leukemias.

Identification of a locus on mouse chromosome 3 involved in differential susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Theiler's virus-induced demyelinating disease results from a chronic infection in the white matter of the central nervous system and provides an excellent model for human multiple sclerosis. Like multiple sclerosis, there are genetic risk factors in disease development, including genes associated with the major histocompatibility complex and with those encoding the beta chain of the T-cell receptor. Comparisons of the susceptible DBA/2 and resistant C57BL/6 strains have indicated an important role for the H-2D locus and for a non-H-2 gene (not involving the beta chain of the T-cell receptor) in differential susceptibility. In the present report, analysis of recombinant-inbred strains (BXD) between the DBA/2 and C57BL/6 strains indicated that this non-H-2 locus is located at the centromeric end of chromosome 3 near (4 +/- 4 centimorgans) the carbonic anhydrase-2 (Car-2) enzyme locus.

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 beta-chain constant gene on chromosome 6.

In some susceptible mouse strains, intracerebral (IC) inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in a persistent infection leading to chronic demyelinating disease. Previous genetic analyses between susceptible SJL/J and resistant C57BL/6 mice indicated a role for multiple unlinked genes in the development of clinical and histopathological disease, including a major influence of the D region of the H-2 complex. In this study, genetic analysis of a different strain combination (susceptible SJL/J and resistant BALB/c) also demonstrates the involvement of multiple genes, but the H-2 genotype (H-2s and H-2d, respectively) does not appear to contribute significantly to susceptibility differences. In both segregation studies and recombinant-inbred (R-I) analysis, clinical and histopathological disease occurs in both H-2s homozygotes and H-2d homozygotes (as well as H-2s/H-2d heterozygotes), with the actual frequency related to the proportion of non-H-2 genome from the susceptible strain. There appear to be at least two non-H-2 genes involved in differential susceptibility of SJL/J and BALB/c to TMEV-induced disease. Analysis of R-I strains generated from BALB/c and SJL/J progenitors indicates linkage of at least one of these non-H-2 genes to those encoding the constant portion of the beta-chain of the T cell receptor on chromosome 6. Many genes may actually be involved, but each strain comparison defines a different subset of these loci--only those at which the two strains in question carry "functionally" different alleles. Thus, different strain comparisons may accent the roles of different genes in resistance to the same infectious organism or disease process. In addition to the genes identified thus far, there may be yet other genes contributing to development of TMEV-induced disease, but their recognition may require analysis of still other strain combinations.