IMMUNOLOGICAL AND PATHOLOGICAL CONSEQUENCES OF MUTATIONS IN BOTH FAS AND FAS LIGAND

The lpr mutation in mice results in premature termination of transcrip tion of the gene encoding the apoptosis-signaling receptor Fas. As a r esult, Lpr mice develop severe lymphoproliferation and lupus-like auto antibodies. Growing evidence suggests that the lpr mutation is ''leaky '' and that low levels of Fas are expressed in lpr mice. To determine if Fas expressed in lpr mice is contributing to apoptosis we generated a novel strain of mice (B6/lprgld) which is homozygous for both the l pr mutation and the gld mutation which encodes nonfunctional Fas ligan d (FasL) protein. If low levels of Fas in B6/lpr mice contribute to ap optosis and lessen the severity of disease, the BG6/lprgld mice, which also lack functional Fast, would be expected to develop a more severe form of disease than B6/lpr mice. Our results revealed no significant increase in either lymphoproliferation or autoimmunity in B6/lprgld m ice compared to B6/lpr or B6/gld mice. Additionally, no increase in su rface expression of Fas was detected by how cytometry on B6/lprgld lym phocytes compared to B6/lpr lymphocytes. However, histological examina tion of B6/lprgld liver revealed a marked increase in lymphocytic infi ltration, compared to livers of B6/lpr and B6/gld mice. Our results su ggest that, while low levels of Fas in lpr mice may not be contributin g to amelioration of lymphoproliferation or autoimmunity, they may be partially protecting the liver from abnormalities which arise in the a bsence of Fas-mediated apoptosis. (C) 1998 Academic Press.