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|Title:||Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody|
|Citation:||Cell, 2020; 180(5):878-894|
|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.|
|Appears in Collections:||Medicine publications|
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