EAE in beta-2 microglobulin-deficient mice: axonal damage is not dependent on MHC-I restricted immune responses.
There is accumulating evidence that CD8-positive (CD8+) T-cells and MHC-I expression may also play a role in neurodegeneration associated with multiple sclerosis (MS). We investigated the role of MHC-I and CD8+ T-cells by studying experimental autoimmune encephalomyelitis (EAE) in beta-2 microglobulin knockout mice induced by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 or whole rat myelin basic protein (rMBP). For both encephalitogens and even after reconstitution of the immune system with MHC-I-positive bone marrow and transfer of mature CD8+ T-cells (iMHC-I+ CD8+ beta2m-/- mice), the disease course in beta2m-/- mice was significantly more severe with a 10-fold increased mortality in the beta2m-/- mice as compared to wild-type C57BL/6 mice. EAE in beta2m-/- mice caused more severe demyelination after immunization with MOG than with rMBP and axonal damage was more marked with rMBP as well as MOG even in iMHC-I+ CD8+ beta2m-/- mice. Immunocytochemical analysis of spinal cord tissue revealed a significant increase in macrophage and microglia infiltration in beta2m-/- and iMHC-I+ CD8+ beta2m-/- mice. The different pattern of T-cell infiltration was underscored by a 2.5-fold increase in CD4-positive (CD4+) T-cells in beta2m-/- mice after induction of MOG 35-55 EAE. We conclude that lack of functional MHC-I molecules and CD8+ T-cells aggravates autoimmune tissue destruction in the CNS. Enhanced axonal damage speaks for pathways of tissue damage independent of CD8+ T-cells and neuronal MHC-I expression.
Linker
Ralf A
RA
Department of Neurology, Clinical Research Group for Multiple Sclerosis, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 11, D-97080 Würzburg, Germany.
Rott
Evelyn
E
Hofstetter
H H
HH
Hanke
T
T
Toyka
Klaus V
KV
Gold
Ralf
R
D000818:Animals; D001369:Axons / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005805:Genes, MHC Class I; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000473:pathology; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D001613:beta 2-Microglobulin