Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis.
OBJECTIVE
Multiple sclerosis (MS) is considered a chronic inflammatory and demyelinating disease of the central nervous system. Evidence that axonal and neuronal pathology contributes to the disease is accumulating, however, the distribution of neuronal injury as well as the underlying mechanisms have not yet been fully clarified. Here, we investigated the role of neuronal cell loss in MS and its animal model, experimental autoimmune encephalomyelitis (EAE).


METHODS
We performed electrophysiological investigations in MS patients, including assessment of compound muscle action potentials and motor unit numbers and quantified neuronal cell loss in human MS samples and different EAE models by high-precision stereology.


RESULTS
Both electrophysiological and morphological analyses indicated a massive loss of lower motor neurons in MS patients. We regularly found dying spinal motor neurons surrounded by CD3+ (CD4+ as well as CD8+) T cells expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We observed a similar degree of damage and immune attack in different variants of EAE; the lower motor neurons were preserved in adoptive transfer EAE induced with TRAIL-deficient T lymphocytes.


CONCLUSIONS
Our study indicates that damage to lower motor neurons and TRAIL-mediated inflammatory neurodegeneration in the spinal cord contribute to MS pathology.
Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Johannes
J
Vogt
Friedemann
F
Paul
Orhan
O
Aktas
Kathrin
K
Müller-Wielsch
Jan
J
Dörr
Susanne
S
Dörr
B Suman
BS
Bharathi
Robert
R
Glumm
Christoph
C
Schmitz
Harry
H
Steinbusch
Cedric S
CS
Raine
Michael
M
Tsokos
Robert
R
Nitsch
Frauke
F
Zipp
D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002452:Cell Count; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology*; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology*; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology
D053221:TNF-Related Apoptosis-Inducing Ligand