Mechanisms of axonal degeneration in EAE--lessons from CNTF and MHC I knockout mice.
The major pathological hallmarks of multiple sclerosis (MS) comprise inflammation, demyelination with associated gliosis and axonal damage, which most likely correlates with persisting disability. Axonal damage can occur by several mechanisms. This article focuses on myelin disintegration and direct immune attack on axons by CD8-positive T-cells as two possible scenarios for axonal injury. As protoypic models, we investigated experimental autoimmune encephalomyelitis (EAE) in ciliary neurotrophic factor gene knockout mice (CNTF-/- mice) with severe myelin pathology and EAE in beta-2 microglobulin gene knockout mice (beta2m-/- mice) lacking CD8-positive T-cells. The results from these studies indicate that the trigger attack for axonal injury even in a well-defined experimental design can be multi-faceted. No single factor seems to be absolutely necessary for the initiation of the process, but they rather act in concert and orchestrate tissue destruction, inflammation and regeneration. Some mechanisms of primary or secondary axonal damage may be shared between inflammatory and degenerative diseases of the nervous system, thereby establishing a link which might be of importance for future therapeutic strategies.
Linker
Ralf A
RA
Department of Neurology, Clinical Research Group for Multiple Sclerosis, University of Würzburg, Josef-Schneider-Strasse 11, D-97080 Würzburg, Germany.
Sendtner
Michael
M
Gold
Ralf
R
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000172:deficiency*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000473:pathology*
D016564:Amyloid beta-Protein Precursor; D020934:Ciliary Neurotrophic Factor; D015395:Histocompatibility Antigens Class I