Single cell analysis of rogue autoantibody producing B cell clones. Rogue B cells

Autoantibodies in the blood are diagnostic of many autoimmune diseases and cause the pathology in some, but it is not understood how lymphocytes evade normal tolerance checkpoints to produce benign or pathogenic autoantibodies. Here we analyse rare circulating B lymphocytes making pathogenic rheumatoid factor autoantibodies in two representative cases of cryoglobulinemic purpura with primary Sjögren’s syndrome. By combining serum antibody proteomics with single cell DNA and RNA sequencing we reveal somatic mutations identical to those found recurrently in lymphoma and leukemia driver genes and show how one of these mutations, in the cullin ubiquitin ligase KLHL6, precipitates the transition from benign to pathogenic autoimmunity by promoting antibody mutation to compromise protein solubility. These results provide direct evidence for a shared pathogenesis of autoimmunity and lymphoid malignancy.