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 - Funding Information:
We thank Charles C Howe, Ashutosh Mangalam, and Veena Taneja for stimulating discussions and Mabel Pierce, Jason Kerkvliet, Michele K. Smart, and Jeff D. Gamez for their excellent technical assistance. This work was supported by the Minnesota Partnership Award for Biotechnology and Medical Genomics. Funds were received from the High-Impact Pilot and Feasibility Award (HIPFA) and Novel Methodology Award (NMDA) from the Mayo Clinic Center for Translational Science Activities (CTSA) and Mayo Clinic CTSA grant number UL1 TR000135 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). We also acknowledge with thanks support from the Applebaum, Hilton, Peterson, and the McNeilus family and the Mayo Center for Multiple Sclerosis and Autoimmune Neurology.
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
VL - 13
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
SN - 1742-2094
IS - 1
M1 - 293
ER -