A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease

Clara Young¹, Mandeep Singh¹, Katherine J L Jackson², Matt A Field³, Timothy J Peters¹, Stefano Angioletti-Uberti⁴, Daan Frenkel⁵, Shyamsundar Ravishankar², Money Gupta⁶, Jing J Wang⁷, David Agapiou⁸, Megan L Faulks², Ghamdan Al-Eryani², Fabio Luciani⁶, Tom P Gordon⁷, Joanne H Reed⁹, Mark Danta¹⁰, Andrew Carr¹¹, Anthony D Kelleher¹², Gregory J Dore¹³, Gail Matthews¹³, Robert Brink¹, Rowena A Bull⁶, Dan Suan¹⁴, Christopher C Goodnow¹⁵

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
² Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
³ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, Smithfield, Cairns, QLD, Australia; Menzies School of Health Research, Darwin, NT, Australia.
⁴ Department of Materials, Imperial College London, London, UK.
⁵ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
⁶ School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
⁷ Department of Immunology, Flinders University and SA Pathology, Bedford Park, Adelaide, SA, Australia.
⁸ The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
⁹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Westmead Institute for Medical Research, Westmead, Sydney, NSW, Australia.
¹⁰ St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
¹¹ Immunology and HIV Unit, St Vincent's Hospital, Sydney, NSW, Australia.
¹² The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; Immunology and HIV Unit, St Vincent's Hospital, Sydney, NSW, Australia.
¹³ St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
¹⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia. Electronic address: d.suan@garvan.org.au.
¹⁵ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia. Electronic address: c.goodnow@garvan.org.au.

PMID: 39818208
DOI: 10.1016/j.immuni.2024.12.011

Free article

A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease

Clara Young et al. Immunity. 2025.

Free article

. 2025 Feb 11;58(2):412-430.e10.

doi: 10.1016/j.immuni.2024.12.011. Epub 2025 Jan 15.

Authors

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
² Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
³ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, Smithfield, Cairns, QLD, Australia; Menzies School of Health Research, Darwin, NT, Australia.
⁴ Department of Materials, Imperial College London, London, UK.
⁵ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
⁶ School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
⁷ Department of Immunology, Flinders University and SA Pathology, Bedford Park, Adelaide, SA, Australia.
⁸ The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
⁹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Westmead Institute for Medical Research, Westmead, Sydney, NSW, Australia.
¹⁰ St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
¹¹ Immunology and HIV Unit, St Vincent's Hospital, Sydney, NSW, Australia.
¹² The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; Immunology and HIV Unit, St Vincent's Hospital, Sydney, NSW, Australia.
¹³ St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
¹⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia. Electronic address: d.suan@garvan.org.au.
¹⁵ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia. Electronic address: c.goodnow@garvan.org.au.

PMID: 39818208
DOI: 10.1016/j.immuni.2024.12.011

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.

Keywords: B lymphocyte; antibody affinity; antigenic mimicry; autoantibody; cryoglobulinemic vasculitis; hepatitis C virus; rheumatoid factor; somatic mutation; superselectivity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease

Affiliations

A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical