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

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

doi:10.1016/j.immuni.2024.12.011

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

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. DoreGail Matthews, Robert Brink, Rowena A. Bull, Dan Suan, Christopher C. Goodnow

College of Medicine and Public Health

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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.

Original language	English
Pages (from-to)	412-430.e10
Number of pages	29
Journal	Immunity
Volume	58
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2024.12.011
Publication status	Published - 11 Feb 2025

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2024.12.011Licence: CC BY

Final published versionFinal published version, 6.28 MBLicence: CC BY

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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., Agapiou, D., Faulks, M. L., Al-Eryani, G., Luciani, F., Gordon, T. P., Reed, J. H., Danta, M., Carr, A., Kelleher, A. D., ... Goodnow, C. 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. https://doi.org/10.1016/j.immuni.2024.12.011

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

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 = "antibody affinity, antigenic mimicry, autoantibody, B lymphocyte, cryoglobulinemic vasculitis, hepatitis C virus, rheumatoid factor, somatic mutation, superselectivity",

author = "Clara Young and Mandeep Singh and Jackson, {Katherine J.L.} and Field, {Matt A.} and Peters, {Timothy J.} and Stefano Angioletti-Uberti and Daan Frenkel and Shyamsundar Ravishankar and Money Gupta and Wang, {Jing J.} and David Agapiou and Faulks, {Megan L.} and Ghamdan Al-Eryani and Fabio Luciani and Gordon, {Tom P.} and Reed, {Joanne H.} and Mark Danta and Andrew Carr and Kelleher, {Anthony D.} and Dore, {Gregory J.} and Gail Matthews and Robert Brink and Bull, {Rowena A.} and Dan Suan and Goodnow, {Christopher C.}",

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doi = "10.1016/j.immuni.2024.12.011",

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Young, C, Singh, M, Jackson, KJL, Field, MA, Peters, TJ, Angioletti-Uberti, S, Frenkel, D, Ravishankar, S, Gupta, M, Wang, JJ, Agapiou, D, Faulks, ML, Al-Eryani, G, Luciani, F, Gordon, TP, Reed, JH, Danta, M, Carr, A, Kelleher, AD, Dore, GJ, Matthews, G, Brink, R, Bull, RA, Suan, D & Goodnow, CC 2025, 'A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease', Immunity, vol. 58, no. 2, pp. 412-430.e10. https://doi.org/10.1016/j.immuni.2024.12.011

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AU - Young, Clara

AU - Singh, Mandeep

AU - Jackson, Katherine J.L.

AU - Field, Matt A.

AU - Peters, Timothy J.

AU - Angioletti-Uberti, Stefano

AU - Frenkel, Daan

AU - Ravishankar, Shyamsundar

AU - Gupta, Money

AU - Wang, Jing J.

AU - Agapiou, David

AU - Faulks, Megan L.

AU - Al-Eryani, Ghamdan

AU - Luciani, Fabio

AU - Gordon, Tom P.

AU - Reed, Joanne H.

AU - Danta, Mark

AU - Carr, Andrew

AU - Kelleher, Anthony D.

AU - Dore, Gregory J.

AU - Matthews, Gail

AU - Brink, Robert

AU - Bull, Rowena A.

AU - Suan, Dan

AU - Goodnow, Christopher C.

PY - 2025/2/11

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N2 - 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.

AB - 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.

KW - antibody affinity

KW - antigenic mimicry

KW - autoantibody

KW - B lymphocyte

KW - cryoglobulinemic vasculitis

KW - hepatitis C virus

KW - rheumatoid factor

KW - somatic mutation

KW - superselectivity

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UR - http://purl.org/au-research/grants/NHMRC/1113904

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DO - 10.1016/j.immuni.2024.12.011

M3 - Article

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AN - SCOPUS:85217106020

SN - 1074-7613

VL - 58

SP - 412-430.e10

JO - Immunity

JF - Immunity

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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