Young, Clara, Singh, Mandeep, Jackson, Katherine J.L., 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, Dan, and Goodnow, Christopher C. (2025) A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease. Immunity, 58 (2). 412-430.e10.

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Abstract

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen. Whole-genome sequencing revealed thousands of somatic mutations, numerically comparable to chronic lymphocytic leukemia and normal memory B cells, but with 1–2 corresponding to driver mutations found recurrently in B cell leukemia and lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility in complex with self-IgG. In this virus-induced autoimmune disease, infection promotes a catastrophic confluence of somatic mutagenesis in the descendants of a single B cell.

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