Clonal expansion of B-cells in human systemic lupus erythematosus: evidence from studies before and after therapeutic B-cell depletion.

ABSTRACT

Anti-B-cell therapy may be beneficial for patients with SLE and active proliferative glomerulonephritis. Using genomic DNA, we examined how rituximab-induced transient B-cell depletion affected the composition of immunoglobulin heavy-chain (Ig-VH/DH/JH) repertoire at the time-point of 33-35% B-cell reconstitution in these patients. Clusters of clonaly-related Ig-VH/DH/JH sequences were evident in all 7 patients with active SLE but in none of 4 healthy subjects studied for comparison. In addition to original somatic mutation(s) shared in the majority of clonaly-related sequences, ongoing mutation suggested expansion of single B-cell precursors and clonal evolution. Otherwise, lupus repertoire was similar to that of healthy subjects with the exception of increased somatic hypermutation. The regenerating repertoire was diverse and comparable to baseline, albeit with fewer somatic mutations but more clonal expansions. Since clonal expansion may lead to preferential survival/growth of potentially autoreactive B-cells further studies are warranted, especially as therapies aiming to reduce B-cell survival emerge.