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

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., and Reed, Joanne H. (2020) Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody. Cell. (In Press)

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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.

Item ID: 62306
Item Type: Article (Research - C1)
ISSN: 1097-4172
Keywords: autoantibody; cryoglobulinemia; lymphoma; rheumatoid factor; single cell omics; somatic mutation; vasculitis
Copyright Information: © 2020 Elsevier Inc.
Funders: The Bill and Patricia Ritchie Foundation, UNSW Cellular Genomics Futures Institute, UNSW Triple I Sphere Consortium, The Rebecca L. Cooper Medical Research Foundation, National Health and Medical Research Council, Australia (NHMRC), NSW Health
Projects and Grants: NHMRC 1142186, NHMRC 1041900, NHMRC 1113904, NHMRC 1090759, NHMRC 1081858, NHMRC 1128416, NSW Health early-to mid-career fellowship
Date Deposited: 19 Feb 2020 03:32
FoR Codes: 06 BIOLOGICAL SCIENCES > 0604 Genetics > 060406 Genetic Immunology @ 50%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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