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Singh, Mandeep; Jackson, Katherine J.L.; Wang, Jing J.; Schofield, Peter; Field, Matt A.; Koppstein, David; Peters, Timothy J.; Burnett, Deborah L.; Rizzetto, Simone; Nevoltris, Damien; Masle-Farquhar, Etienne; Faulks, Megan L.; Russell, Amanda; Gokal, Divya; Hanioka, Asami; Horikawa, Keisuke; Colella, Alexander D.; Chataway, Timothy K.; Blackburn, James; Mercer, Tim R.; Langley, David B.; Goodall, D. Margaret; Jefferis, Roy; Gangadharan Komala, Muralikrishna; Kelleher, Anthony D.; Suan, Dan; Rischmueller, Maureen; Christ, Daniel; Brink, Robert; Luciani, Fabio; Gordon, Tom P.; Goodnow, Christopher C.; Reed, Joanne H.
Cell, 03/2020, Letnik: 180, Številka: 5Journal Article
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. Display omitted •Single-cell omics reveal rare cells making a common pathogenic human autoantibody•Antibody mutations cause pathogenicity by phase transition to insoluble aggregates•Lymphoma driver mutations are present in cells making pathogenic autoantibodies•Driver mutations dysregulate NF-κB signaling, cell cycle, and antibody mutation Integrated proteomics and single-cell analysis reveal rogue cell clones with lymphoma driver mutations producing damaging antibodies with the propensity for phase transition into insoluble antibody-autoantigen complexes.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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