TY - JOUR
T1 - Human class I major histocompatibility complex alleles determine central nervous system injury versus repair
AU - Wootla, Bharath
AU - Denic, Aleksandar
AU - Watzlawik, Jens O.
AU - Warrington, Arthur E.
AU - Zoecklein, Laurie J.
AU - Papke-Norton, Louisa M.
AU - David, Chella
AU - Rodriguez, Moses
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/11/17
Y1 - 2016/11/17
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - Human leukocyte antigen
KW - Major histocompatibility complex
KW - Picornavirus
KW - Theiler's murine encephalomyelitis virus
KW - Virus persistence
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U2 - 10.1186/s12974-016-0759-4
DO - 10.1186/s12974-016-0759-4
M3 - Article
C2 - 27855706
AN - SCOPUS:85003666517
SN - 1742-2094
VL - 13
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 293
ER -