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(American Journal of Pathology. 2006;169:999-1011.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050791

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

Correlation with Early Reversible Axonal Dysfunction in Acute Experimental Autoimmune Encephalomyelitis

From the BloodCenter of Wisconsin, Blood Research Institute, Milwaukee; and the Department of Microbiology and Molecular Genetics, The Medical College of Wisconsin, Milwaukee, Wisconsin

During the course of the central nervous system autoimmune disease multiple sclerosis (MS), damage to myelin leads to neurological deficits attributable to demyelination and conduction failure. However, accumulating evidence has indicated that axonal injury is also a predictor of MS clinical disease. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we examined whether axonal dysfunction occurred early in disease and correlated with disease symptoms. We tracked axons during EAE by using transgenic mice that express yellow fluorescent protein (YFP) in neurons. At the onset of disease, we observed a loss of YFP fluorescence in the spinal cord in areas that coincided with immune cell infiltration, before prominent demyelination. These inflammatory lesions also exhibited evidence of axonal injury but not axonal loss. During the recovery phase of EAE, the return of YFP fluorescence occurred in parallel with the resolution of inflammation. Using in vitro cultured neurons expressing YFP, we demonstrated that encephalitogenic T cells alone directed the destabilization of microtubules within neurites, resulting in a change in the pattern of YFP fluorescence. This study provides evidence that encephalitogenic T cells directly cause reversible axonal dysfunction at the onset of neurological deficits during an acute central nervous system inflammatory attack.

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