Increased TUNEL staining in brains of autoimmune Fas-deficient mice.
Profound changes in brain morphology and behavior coincide with the spontaneous development of systemic autoimmune/inflammatory disease in Fas-deficient MRL-lpr mice. The dendrites atrophy, the density of hippocampal and cortical neurons decreases, and an anxious/depressive-like behavior emerges while lymphoid cells infiltrate into the choroid plexus of MRL-lpr mice. We hypothesized that the inherited lack of the Fas-dependent anti-inflammatory mechanism would lead to unsuppressed immune activity, characterized by reduced apoptosis in the MRL-lpr brain. Using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeled (TUNEL) method as an indicator of apoptosis, a surprisingly high incidence of TUNEL-positive cells was observed in the hippocampus, choroid plexus and periventricular regions of MRL-lpr mice, 5-10-fold higher than that found in the MRL +/+ control brain. Immunostaining with anti-CD3, CD4 and CD8 monoclonal antibodies showed limited overlap between CD-positive and TUNEL-positive cells, suggesting that the dying cells are for the most part (approximately 70%) not T-lymphocytes. Although further characterization of the phenotype of the dying cells and the mechanism of cell death are required, the present results suggest the involvement of a Fas-independent apoptotic process in neurodegeneration induced by systemic autoimmune disease.
Sakic
B
B
Department of Psychiatry and Behavioural Neurosciences, McMaster University, HSC 4N77A, 1200 Main Street, Hamilton, Ontario, Canada. sakic@mcmaster.ca
Maric
I
I
Koeberle
P D
PD
Millward
J M
JM
Szechtman
H
H
Maric
D
D
Denburg
J A
JA
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis; D001284:Atrophy; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology*; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D002831:Choroid Plexus / Q000276:immunology / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018613:Microscopy, Confocal; D013601:T-Lymphocytes; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019014:fas Receptor