A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease
Date
2025
Authors
Young, C.
Singh, M.
Jackson, K.J.L.
Field, M.A.
Peters, T.J.
Angioletti-Uberti, S.
Frenkel, D.
Ravishankar, S.
Gupta, M.
Wang, J.J.
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Journal article
Citation
Immunity, 2025; 58(2):412-430.e10
Statement of Responsibility
Clara Young, Mandeep Singh, Katherine J.L. Jackson, Matt A. Field, Timothy J. Peters, Stefano Angioletti-Uberti, Daan Frenkel, Shyamsundar Ravishankar, Money Gupta, Jing J. Wang, David Agapiou, Megan L. Faulks, Ghamdan Al-Eryani, Fabio Luciani, Tom P. Gordon, Joanne H. Reed, Mark Danta, Andrew Carr, Anthony D. Kelleher, Gregory J. Dore, Gail Matthews, Robert Brink, Rowena A. Bull, Dan Suan, Christopher C. Goodnow
Conference Name
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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©2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).