Fas-mediated apoptosis eliminates B cells that acquire self-reactivity during the germinal center response to NP

C57B1/6 mice with the Ipr mutation of Fas (CD95) were tested for deviation from the genetically restricted antibody response to the hapten 4-hydroxy-3 -nitrophenyl acetyl (NP). lambda 1+ germinal centers (GC) with the canonica l v186.2 VH gene element develop in lpr/lpr mice with the same time course as in wild-type (+/+) mice. In contrast to +/+ mice, however, lambda 1+ GC persist in the spleens of lpr/lpr mice 25 days after immunization. Virtuall y all of the lambda 1+ GC are reactive with NP 10 days after immunization. Sixteen days after immunization, however, many of the lambda 1+ GC are not reactive with NP, and few of the lambda 1+ GC are reactive with NP 25 days after immunization. The V-H gene elements of three lambda 1+NP- QC 25 days after immunization are derived by somatic mutation of v186.2, but have lost reactivity with NP. The mutated VDJs from these GC react with cells in spl een sections from +/+ and lpr/lpr mice, indicating that they represented se condary antibody responses induced by self antigens that are available as p resented antigen. These data indicate that Fas-mediated apoptosis serves to eliminate a (limited) population of B cells that acquire reactivity to "se lf antigens" by somatic mutation of VDJs in the GC. (C) 2000 Academic Press .