Increased TUNEL staining in brains of autoimmune Fas-deficient mice

Profound changes in brain morphology and behavior coincide with the spontan eous development of systemic autoimmune/inflammatory disease in Fas-deficie nt MRL-lpr mice. The dendrites atrophy, the density of hippocampal and cort ical neurons decreases, and an anxious/depressive-like behavior emerges whi le lymphoid cells infiltrate into the choroid plexus of MRL-lpr mice. We hy pothesized that the inherited lack of the Fas-dependent anti-inflammatory m echanism would lead to unsuppressed immune activity, characterized by reduc ed apoptosis in the MRL-lpr brain. Using the terminal deoxynucleotidyl tran sferase-mediated dUTP nick-end labeled (TUNEL) method as an indicator of ap optosis, 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. Immuno staining with anti-CD3, CD4 and CD8 monoclonal antibodies showed limited ov erlap between CD-positive and TUNEL-positive cells, suggesting that the dyi ng cells are for the most part (similar to 70%) not T-lymphocytes. Although further characterization of the phenotype of the dying cells and the mecha nism of cell death are required, the present results suggest the involvemen t of a Fas-independent apoptotic process in neurodegeneration induced by sy stemic autoimmune disease. (C) 2000 Elsevier Science B.V. All rights reserv ed.