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

Bharath Wootla, Aleksandar Denic, Jens O. Watzlawik, Arthur E. Warrington, Laurie J. Zoecklein, Louisa M. Papke-Norton, Chella David, Moses Rodriguez

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, β2m(0)) and class II-deficient (mouse Aβ(0)) 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 Aβ(0).β2m(0) 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.