Theiler's virus persistence and demyelination in major histocompatibility complex class II-deficient mice

Abstract

Mice with targeted disruption of the A ␤ gene of major histocompatibility complex class II molecules (Ab o ) were used to investigate the role of class II gene products in resistance or susceptibility to virus-induced chronic demyelination in the central nervous system (CNS). Class II-deficient mice from the resistant H-2 b [H-2 b (Ab o )] and nonmutant H-2 b backgrounds were infected with Theiler's murine encephalomyelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2 b mice had cleared the virus within 21 days, whereas the other 2 mice had low titers. In contrast, all class II-deficient Ab o mice had high virus titers for up to 90 days after infection (4.30 log 10 to 6.18 log 10 PFU per g of CNS tissue). Virus antigens and RNA were localized to the brains (cortex, hippocampus, thalamus, and brain stem) and spinal cords of Ab o mice. Colocalization identified persistent Theiler's murine encephalomyelitis virus in oligodendrocytes and astrocytes but not in macrophages. There was demyelination in 11 of 23 and 6 of 9 Ab o mice 45 and 90 days after virus infection, respectively, whereas no demyelination was observed in infected nonmutant H-2 b mice. Demyelinating lesions in Ab o mice showed virus-specific CD8 ؉ T cells and macrophages but no CD4 ؉ T cells. Spasticity and paralysis were observed in chronically infected Ab o mice but not in the nonmutant H-2 b mice. These findings demonstrate that class II gene products are required for virus clearance from the CNS but not for demyelination and neurologic disease.

Interleukin-6 Protects Anterior Horn Neurons from Lethal Virus-Induced Injury

“…Whole blood was collected from mice at time they were killed, and sera was isolated and stored at Ϫ80°C. Total serum IgGs and IgMs against TMEV were assessed by ELISA as described previously (Njenga et al, 1996). Virus was adsorbed to 96-well plates (Immulon II; Dynatech Laboratories, Chantilly, VA) and then blocked with 1% bovine serum albumin (BSA) (Sigma St. Louis, MO) in PBS.…”

CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology

“…Although these data seem to rigorously support the role of CD4 C Th1 cells in both initiation and progression of TMEV-IDD, there are also a number of published reports suggesting the same is true for CD8 C T cells (Rodriguez et al, 1986a;Rodriguez and Sriram, 1988;Matloubian et al, 1994;Njenga et al, 1996;Murray et al, 1998). However, as the majority of these studies were conducted using mice on a resistant genetic background (C57BL/6 and 129/J), in this study we sought to determine the outcome of the TMEV-IDD disease phenotype in the absence of CD8 C T cells in the highly susceptible SJL/J mice that were de cient in the expression of¯2M.…”

“…There is considerable evidence from our own lab, as well as others, that indicates a critical role for CD4 C Th1 cells in mediating both the initial and chronic pathogenesis of TMEV-IDD in the susceptible SJL/J strain, as demonstrated by antibody depletion studies (Rodriguez et al, 1986a;Friedmann et al, 1987;Welsh et al, 1987), the correlation of delayed-type hypersensitivity (DTH) responses with the severity of disease (Miller et al, 1997), and the increasing amounts of CD4 C Th1derived pro-in ammatory cytokines expressed in the CNS throughout disease progression (Begolka et al, 1998). Despite these signi cant ndings, there also exist numerous lines of often contradictory evidence from similar studies conducted in resistant C57BL/6 mice with gene deletions to additionally support the role of CD8 C T cells, not only in viral clearance and protection but also in promoting the demyelinating process (Rodriguez et al, 1986a;Rodriguez and Sriram, 1988;Fiette et al, 1993;Pullen et al, 1993;Njenga et al, 1996;Murray et al, 1998).…”

Remyelination as Neuroprotection

“…These animals failed to develop significant clinical signs of functional deficit as measured by hind-limb motor-evoked potentials, spontaneous vertical and horizontal movement assessment, rotarod performance, and activity wheel behavior (Fiette et al, 1993;Pullen et al, 1993;Rivera-Quinones et al, 1998;Rodriguez et al, 1993;Ure and Rodriguez, 2002). On the other hand, mice of the same haplotype that were deficient in expression of MHC class II (C57BL/6 × 129/J Ab 0 ) developed not only extensive demyelination but also severe neurological impairment, and were, in fact, frequently moribund by 120 days postinfection (Njenga et al, 1996;Rivera-Quinones et al, 1998). Our findings indicate that physiological function was likely preserved secondary to the upregulation and redistribution of sodium channels along demyelinated axons.…”