The lpr gene encodes a defective form of the fas gene that mediates ap
optosis, and its expression results in autoantibodies and massive lymp
hadenopathy. bcl-2, another gene locus that affects programmed cell de
ath, acts to inhibit apoptosis. Since multiple mechanisms controlling
programmed cell death may contribute to systemic autoimmunity, the eff
ect of the bcl-2 transgene on the lpr model was examined by crossing b
cl-2 transgenic and C57BL/6-lpr mice. Compared with bcl-2(-)/lpr mice,
bcl-2(+)/lpr showed dramatic increases in lymphadenopathy and T cell
accumulation, but not in autoantibodies or B cell numbers. Short term
transfer studies demonstrated that double negative T cells normally ha
ve a limited lifespan, and their survival is enhanced by the bcl-2 tra
nsgene. Thus, defects in separate apoptosis mechanisms may combine to
produce enhanced pathologic effects.