PRECURSOR B-CELLS FOR AUTOANTIBODY PRODUCTION IN GENOMICALLY FAS-INTACT AUTOIMMUNE-DISEASE ARE NOT SUBJECT TO FAS-MEDIATED IMMUNE ELIMINATION

The Fas/Fas ligand (FasL) system participates in regulation of the imm une system through the apoptotic process, However, the extent to which abnormalities in this system are involved in the loss of self-toleran ce and development of autoimmune disease not associated with Fas/FasL mutations remains unknown. The present study addresses this issue in F as/FasL-intact, systemic lupus erythematosus (SLE)-prone (NZB x NZW) ( NZB/W) F-1 mice, While splenic B cells from 2-month-old mice before ov ert SLE expressed Fas poorly, in vitro Stimulation with an agonistic a nti-CDc40 mAb up-regulated their Fas expression, thus revealing the ex istence of two populations: one was Fas(high) and highly susceptible t o anti-Fas mAb-induced apoptosis, and the other was Fas(low) and apopt osis-resistant. The Fas(low) cells were included in the CD5(+) B cell subpopulation and contained most of the cells that produced IgM anti-D NA antibodies, The isotype of anti-DNA antibodies switches from IgM to IgG in NZB/W F-1 mice at ages beginning at about 6 months. These IgG anti-DNA antibodies were produced almost exclusively by a subpopulatio n of splenic B cells that spontaneously expressed low levels of Fas in vivo and were apoptosis-resistant. The findings indicate that precurs or B cells for autoantibody production and presumably autoantibody-sec reting cells in these mice are relatively resistant to Fas-mediated ap optosis, a finding supporting the concept that abnormalities of Fas-me diated apoptotic process are involved in the development of autoreacti ve B cells in Fas/FasL-intact autoimmune disease.