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

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. HL A-DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expre ssion of MHC class I (beta(2)m) and class II (H2-A(beta)) molecules. Follow ing Theiler's murine encephalomyelitis virus (TMEV) infection, we assessed survival, virus persistence, demyelination, and clinical disease. Mice lack ing expression of endogenous class I and class II molecules (beta(2)m degre es A beta degrees mice) died 3 to 4 weeks postinfection (p.i.) due to overw helming virus replication in neurons. beta(2)m degrees A beta degrees DQ6 a nd beta(2)m degrees A beta degrees DQ8 mice had increased survival and decr eased gray matter disease and virus replication compared to nontransgenic l ittermate controls. Both beta(2)m degrees A beta degrees DQ6 and beta(2)m d egrees A beta degrees DQ8 mice developed chronic virus persistence in glial cells of the white matter of the spinal cord, with greater numbers of viru s antigen-positive cells in beta(2)m degrees A beta degrees DQ8 than in bet a(2)m degrees AP degrees DQ6 mice. At day 45 p.i., the demyelinating lesion s in the spinal cord of beta(2)m degrees A beta degrees DQ8 were larger tha n those in the beta(2)m degrees A beta degrees DQ6 mice. Earlier and more p rofound neurologic deficits were observed in beta(2)m degrees A beta degree s DQ8 mice compared to beta(2)m degrees A beta degrees DQ6 mice, although b y 120 days p.i. both strains of mice showed similar extent of demyelination and neurologic deficits. Delayed-type hypersensitivity and antibody respon ses to TMEV demonstrated that the mice mounted class Ii-mediated cellular a nd humoral immune responses. The results are consistent with the hypothesis that rates of progression of demyelination and neurologic deficits are rel ated to the differential ability of DQ6 and DQ8 transgenes to modulate the immune response and control virus.