Human class I major histocompatibility complex alleles determine central nervous system injury versus repair

We investigated the role of human HLA class I molecules in persistent central nervous system (CNS) injury versus repair following virus infection of the CNS.

Human class I A11⁺ and B27⁺ transgenic human beta-2 microglobulin positive (Hβ2m⁺) mice of the H-2 ^b background were generated on a combined class I-deficient (mouse beta-2 microglobulin deficient, β2m⁰) and class II-deficient (mouse Aβ⁰) phenotype. Intracranial infection with Theiler's murine encephalomyelitis virus (TMEV) in susceptible SJL mice results in acute encephalitis with prominent injury in the hippocampus, striatum, and cortex.

Following infection with TMEV, a picornavirus, the Aβ⁰.β2m⁰ mice lacking active immune responses died within 18 to 21 days post-infection. These mice showed severe encephalomyelitis due to rapid replication of the viral genome. In contrast, transgenic Hβ2m mice with insertion of a single human class I MHC gene in the absence of human or mouse class II survived the acute infection. Both A11⁺ and B27⁺ mice significantly controlled virus RNA expression by 45 days and did not develop late-onset spinal cord demyelination. By 45 days post-infection (DPI), B27⁺ transgenic mice showed almost complete repair of the virus-induced brain injury, but A11⁺ mice conversely showed persistent severe hippocampal and cortical injury.

The findings support the hypothesis that the expression of a single human class I MHC molecule, independent of persistent virus infection, influences the extent of sub frequent chronic neuronal injury or repair in the absence of a class II MHC immune response.