Contribution of VH replacement products to the generation of autoantibodies in systemic lupus erythematosus (44.19)

Abstract

Abstract Systemic lupus erythematosus (SLE) is characterized by the over production of high affinity autoantibodies that play important roles in SLE pathogenesis. However, it is not clear how these antibodies are generated and selected during the course of lupus. Our sequence analysis show that VH replacement products are highly enriched in IgH genes derived from different autoimmune diseases, including SLE. To gain insight into the mechanisms responsible for autoantibody generation in SLE, we performed single cell PCR analysis to study the functional antibody repertoires in active SLE patients. Analysis of 102 recombinant antibodies derived from the naive B cells and plasmablasts of the SLE patients show that 4.8% of the antibodies derived from naïve B cells and 26.7% of the antibodies derived from plasmablasts are autoreactive. Detailed sequence analysis reveal that in the plasmablasts of two SLE patients, VH replacement products contribute to more than 30% of IgH genes. These VH replacement products have long CDR3 regions enriched with charged amino acids, and more than 60% of them encode anti-nuclear or poly-reactive autoantibodies. These studies provide the first evidence that VH replacement products directly contribute to the generation of autoantibodies in SLE.