APOPTOSIS ABNORMALITIES OF SPLENIC LYMPHOCYTES IN AUTOIMMUNE LPR AND GLD MICE

The murine gene lpr encodes an aberrant form of the apoptosis-inducing receptor Fas. The gene gld, which causes an autoimmune syndrome pheno typically identical to that caused by lpr, encodes a mutant Fas ligand . Because the lpr gene must be expressed in both T and B cells to prod uce autoimmune disease, it might be anticipated that apoptosis abnorma lities would be present in both. Therefore, we quantitated apoptosis i n T and B cells from lpr, gld, and normal mice in a short-term in vitr o culture system. Freshly isolated spleen cells from normal, lpr, or g ld mice showed little or no apoptosis as assessed by quantitative DNA flow cytometry. However, after overnight culture, both T and B cells s howed substantial spontaneous apoptosis. Such apoptosis increased stri kingly with age in normal but not in autoimmune B cells. CD23(low) B c ells, which are prominent in lpr and gld mice, were particularly notab le for high levels of programmed cell death in normal mice. The apopto sis caused by the gld defect could not be corrected by coculture with normal spleen cells. The persistence with age of low levels of B cell apoptosis in lpr and gld mice presumably reflects deficient Fas/Fas li gand interactions. The further localization of the B cell apoptosis de fect to the unusual CD23(low) B cells, which accumulate in lpr and gld mice, adds to the evidence that these cells may be of critical import ance to autoimmunity.