Trigger mechanisms of autoantibody production

The random combinatorial assembly of Ig variable (V) gene elements leads to the generation of a proportion of antibodies with high affinity to self. Under normal conditions, the corresponding B-cells will be clonally deleted, rendered silent, or switched to a different specificity. In systemic autoimmunity, however, anti-self high affinity antibodies are overexpressed. We have been trying to uncover the molecular choreography that underlies the production of aggressive autoantibodies in SLE. Here, we studied B-cell clones producing anti-DNA autoantibodies that bear the human pathogenic 0-81 idiotypic marker, an idiotype present in 72% of immune complexes, and in 100% of renal eluates from patients with active SLE. In contrast to other lupus idiotypes, this marker is present in the circulation of most patients with active lupus nephritis, but not in inactive SLE or healthy subjects. Molecular cloning, nucleotide sequencing, and comparative genomic PCR revealed that lupus antibody variable genes incurred extensive somatic selection events. There is also evidence that the corresponding B-cells underwent essential primary light-chain variable rearrangements. We conclude that, in SLE, B-cells are the target of antigenic selection. We also propose that a subset of B-cells may be unable to revise their receptor and extinguish their high affinity for self.