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

in Immunity by 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

TLDR

  • The study analyzed the origins of HCV-cryovas by tracing the evolution of pathogenic RF autoantibodies in patients and found that infection promotes somatic mutagenesis in B cells.
  • The study revealed recurring antibody variable domain combinations that bind self-IgG and thousands of somatic mutations in B cells.
  • The findings provide insights into the origins of HCV-cryovas and potential therapeutic targets for the 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.

Overview

  • The study aimed to analyze the unexplained association between infection and autoimmune disease by tracing the evolution of pathogenic rheumatoid factor (RF) autoantibodies in patients with hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas).
  • Deep single-cell multi-omic analysis was used to study B cell somatic mutation in four HCV-cryovas patients, revealing three sources of mutations that converged to drive the accumulation of a large disease-causing clone.
  • The study focused on understanding the origins of HCV-cryovas, a virus-induced autoimmune disease, and the role of infection in promoting somatic mutagenesis in B cells.

Comparative Analysis & Findings

  • Deep single-cell multi-omic analysis revealed three sources of B cell somatic mutation that converged to drive the accumulation of a large disease-causing clone in HCV-cryovas patients.
  • The study found that recurring antibody variable domain combinations created by V(D)J recombination bound self-immunoglobulin G (IgG) but not viral E2 antigen, indicating a role for self-reactive antibodies in the disease.
  • Whole-genome sequencing revealed thousands of somatic mutations, 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.

Implications and Future Directions

  • The study's findings provide insights into the origins of HCV-cryovas and the role of infection in promoting somatic mutagenesis in B cells.
  • Future studies can investigate the mechanisms by which self-reactive antibodies contribute to the disease and explore novel therapeutic strategies targeting these antibodies.
  • The discovery of recurring antibody variable domain combinations and V(D)J hypermutation provides opportunities for developing diagnostic tests and therapeutic interventions for HCV-cryovas.
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