HLA-DQ polymorphism influences progression of demyelination and neurologic deficits in a viral model of multiple sclerosis

Kevin D. Pavelko, Kristen M. Drescher, Dorian B. McGavern, Chella S. David, Moses Rodriguez

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The importance of genetic susceptibility in determining the progression of demyelination and neurologic deficits is a major focus in neuroscience. We studied the influence of human leukocyte antigen (HLA)-DQ polymorphisms on disease course and neurologic impairment in virus-induced demyelination. HLA- DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expression of MHC class I (β2m) and class II (H2-A(β)) molecules. Following Theiler's murine encephalomyelitis virus (TMEV) infection, we assessed survival, virus persistence, demyelination, and clinical disease. Mice lacking expression of endogenous class I and class II molecules (β2m°Aβ° mice) died 3 to 4 weeks postinfection (p.i.) due to overwhelming virus replication in neurons. β2m°Aβ°DQ6 and β2m°Aβ°DQ8 mice had increased survival and decreased gray matter disease and virus replication compared to nontransgenic littermate controls. Both β2m°Aβ°DQ6 and β2m°Aβ°DQ8 mice developed chronic virus persistence in glial cells of the white matter of the spinal cord, with greater numbers of virus antigen-positive cells in β2m°Aβ°DQ8 than in β2m°Aβ°DQ6 mice. At day 45 p.i., the demyelinating lesions in the spinal cord of β2m°Aβ°DQ8 were larger than those in the β2m°Aβ°DQ6 mice. Earlier and more profound neurologic deficits were observed in β2m°Aβ°DQ8 mice compared to β2m°Aβ°DQ6 mice, although by 120 days p.i. both strains of mice showed similar extent of demyelination and neurologic deficits. Delayed- type hypersensitivity and antibody response to TMEV demonstrated that the mice mounted class II-mediated cellular and humoral immune responses. The results are consistent with the hypothesis that rates of progression of demyelination and neurologic deficits are related to the differential ability of DQ6 and DQ8 transgenes to modulate the immune response and control virus.

Original languageEnglish (US)
Pages (from-to)495-509
Number of pages15
JournalMolecular and Cellular Neurosciences
Volume15
Issue number6
DOIs
StatePublished - Jun 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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