Self-reactive B cells traverse a perfect storm of somatic mutagenesis to cause a virus-induced autoimmune disease

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-CV). We traced the evolution of the pathogenic rheumatoid factor (RF) autoantibodies in four HCV-CV patients by deep single cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive accumulation of a large disease causing clone. A sensitive method for quantifying low affinity binding revealed three recurring heavy/light chain combinations created byV(D)Jrecombination bound self IgG but not viral E2 antigen. Whole genome sequencing revealed accumulation of thousands of somatic mutations, at levels comparable to CLL and normal memory B cells, but with 1-2 corresponding to driver mutations found recurrently in B cell leukemia/lymphoma.V(D)Jhypermutation created autoantibodies with compromised solubility in complex with self-IgG. In this virus-induced autoimmune disease, infection promotes a perfect storm of somatic mutagenesis in the descendants of a single B cell We performed single cell RNA sequencing analysis of CD19+CD20+B cells sorted from the blood of a patient with hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-CV), after HCV clearance with direct acting anti-viral (DAA) therapy. Gene expression (10X 3’) and immunoglobulin receptor sequencing (RAGE-seq) were performed for each individual B cell.