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Type: Journal article
Title: Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody
Author: Singh, M.
Jackson, K.J.
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.
Mercer, T.R.
et al.
Citation: Cell, 2020; 180(5):878-894
Publisher: Elsevier
Issue Date: 2020
ISSN: 0092-8674
Statement of
Mandeep Singh, Katherine J.L. Jackson, Jing J. Wang, Peter Schofield, Matt A. Field ... Maureen Rischmueller ... et al.
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.
Keywords: autoantibody; cryoglobulinemia; lymphoma; rheumatoid factor; single cell omics; somatic mutation; vasculitis
Rights: © 2020 Elsevier Inc.
RMID: 1000015158
DOI: 10.1016/j.cell.2020.01.029
Appears in Collections:Medicine publications

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