Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody

Journal Publication ResearchOnline@JCU
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;Komala, Muralikrishna Gangadharan;Kelleher, Anthony D.;Suan, Dan;Rischmueller, Maureen;Christ, Daniel;Brink, Robert;Luciani, Fabio;Gordon, Tom P.;Goodnow, Christopher C.;Reed, Joanne H.
Matt Field
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.

Journal

Cell

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Volume

180

ISBN/ISSN

1097-4172

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Issue

5

Pages Count

37

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Publisher

Elsevier

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DOI

10.1016/j.cell.2020.01.029