The accumulated VH replacement products contribute to the generation of auto/polyreactive antibodies in systemic lupus erythematosus (P1721) (159.3)

Systemic lupus erythematosus (SLE) is characterized by the over-production of high affinity autoantibodies. However, it is not clear how these autoantibodies are generated and selected. VH replacement is originally considered as a receptor editing process to change unwanted non-functional immunoglobulin heavy chain (IgH) genes or IgH genes encoding self reactive BCRs. Our sequence analysis shows that VH replacement products are highly enriched in IgH genes derived from different autoimmune diseases, including SLE. In this study, we performed single cell RT-PCR to study the functional antibody repertoires in active SLE patients. Analysis of 180 recombinant antibodies derived from SLE patients showed that 19.0% of the antibodies derived from naïve B cells and 56.9% of the antibodies derived from plasmablasts are autoreactive. In contrast, only 7.7% and 17.4% of the antibodies derived from naïve B cells and plasmablast B cells are autoreactive in healthy donors. The VH replacement products are significantly increased in IgH genes obtained from SLE patients (20%) compared to that in healthy controls (10%). Importantly, the accumulated VH replacement products in SLE patients have long CDR3 regions enriched with positively charged amino acids; 74% of them directly encode anti-nuclear antigen or polyreactive antibodies. Based on these results, we conclude that the accumulated VH replacement products in SLE patients contribute to the generation of auto/polyreactive antibodies in SLE.