Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

Mandeep Singh, Katherine J.L. Jackson, Jing J. Wang, Peter Schofield, Matt A. Field, David Koppstein, Timothy J. Peters, Deborah L. Burnett, Simone Rizzetto, Damien Nevoltris, Etienne Masle-Farquhar, Megan L. Faulks, Amanda Russell, Divya Gokal, Asami Hanioka, Keisuke Horikawa, Alexander D. Colella, Timothy K. Chataway, James Blackburn, Tim R. MercerDavid B. Langley, D. Margaret Goodall, Roy Jefferis, Muralikrishna Gangadharan Komala, Anthony D. Kelleher, Dan Suan, Maureen Rischmueller, Daniel Christ, Robert Brink, Fabio Luciani, Tom P. Gordon, Christopher C. Goodnow, Joanne H. Reed

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.

Original languageEnglish
Pages (from-to)878-894
Number of pages37
JournalCell
Volume180
Issue number5
DOIs
Publication statusPublished - 5 Mar 2020

Keywords

  • autoantibody
  • cryoglobulinemia
  • lymphoma
  • rheumatoid factor
  • single cell omics
  • somatic mutation
  • vasculitis

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    Singh, M., Jackson, K. J. L., Wang, J. J., Schofield, P., Field, M. A., Koppstein, D., Peters, T. J., Burnett, D. L., Rizzetto, S., Nevoltris, D., Masle-Farquhar, E., Faulks, M. L., Russell, A., Gokal, D., Hanioka, A., Horikawa, K., Colella, A. D., Chataway, T. K., Blackburn, J., ... Reed, J. H. (2020). Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody. Cell, 180(5), 878-894. https://doi.org/10.1016/j.cell.2020.01.029