Author:
Young Clara,Singh Mandeep,Jackson Katherine JL,Field Matt A,Peters Timothy J,Angioletti-Uberti Stefano,Frenkel Daan,Ravishankar Shyamsundar,Gupta Money,Wang Jing J,Agapiou David,Faulks Megan L,Al-Eryani Ghamdan,Luciani Fabio,Gordon Tom P,Reed Joanne H,Danta Mark,Carr Andrew,Kelleher Anthony D,Dore Gregory J,Matthews Gail,Brink Robert,Bull Rowena A,Suan Daniel,Goodnow Christopher C
Abstract
SummaryThe 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 (RhF) 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 this virus-induced autoimmune disease, infection promotes a perfect storm of somatic mutagenesis in the descendants of a single B cell.
Publisher
Cold Spring Harbor Laboratory