Background Advances in single cell genomics have illuminated aberrant cells with striking transcriptional differences in patients with systemic lupus erythematosus compared to healthy individuals. However, it is not clear whether the aberrant cells are directly responsible for pathology or bystanders that have become aberrant in response to an inflammatory environment. This is an important distinction because safer and more effective treatments rely on identifying and eliminating pathogenic cells. The goal of this study was to molecularly characterise the cells that produce pathogenic autoantibodies and determine how they differ to their normal counterparts.

Methods A multi-omics approach was employed to identify pathogenic autoreactive B-cells, which linked mass spectrometry sequencing of serum autoantibody with massively parallel sequencing of immunoglobulin expressed by circulating B-cells. Single cell sequencing was performed to compare gene expression and mutation in pathogenic and normal B-cells.

Results Rare circulating B-cells making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations in immunoglobulin regions. The pathogenic cells had a distinct gene expression profile similar to that previously observed in CD21-low atypical memory B-cells.

Conclusions The detailed analysis of pathogenic B-cells reveals insights into disease pathology and therapeutic targets for precision medicine approaches.