Fas-Mediated Apoptosis Eliminates B Cells That Acquire Self-Reactivity during the Germinal Center Response to NP

C57Bl/6 mice with the lpr mutation of Fas (CD95) were tested for deviation from the genetically restricted antibody response to the hapten 4-hydroxy-3-nitrophenyl acetyl (NP). λ1+ germinal centers (GC) with the canonical 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, λ1+ GC persist in the spleens of lpr/lpr mice 25 days after immunization. Virtually all of the λ1+ GC are reactive with NP 10 days after immunization. Sixteen days after immunization, however, many of the λ1+ GC are not reactive with NP, and few of the λ1+ GC are reactive with NP 25 days after immunization. The VH gene elements of three λ1+NP− GC 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 spleen sections from +/+ and lpr/lpr mice, indicating that they represented secondary antibody responses induced by self antigens that are available as presented antigen. These data indicate that Fas-mediated apoptosis serves to eliminate a (limited) population of B cells that acquire reactivity to “self antigens” by somatic mutation of VDJs in the GC.