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Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody.
- Source :
-
Cell [Cell] 2020 Mar 05; Vol. 180 (5), pp. 878-894.e19. Date of Electronic Publication: 2020 Feb 13. - Publication Year :
- 2020
-
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.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Autoantibodies immunology
Autoimmune Diseases immunology
Autoimmune Diseases pathology
B-Lymphocytes pathology
CARD Signaling Adaptor Proteins genetics
Carrier Proteins genetics
Clonal Evolution genetics
Clonal Evolution immunology
Cyclin D3 genetics
Guanylate Cyclase genetics
Humans
Immediate-Early Proteins genetics
Immunoglobulin Variable Region genetics
Immunoglobulin Variable Region immunology
Inhibitor of Differentiation Proteins genetics
Lymphoma immunology
Lymphoma pathology
Mice
Mutation genetics
Mutation immunology
Neoplasm Proteins genetics
Sequence Analysis, DNA methods
Sequence Analysis, RNA methods
Single-Cell Analysis methods
Tumor Necrosis Factor alpha-Induced Protein 3 genetics
Tumor Suppressor Proteins genetics
V(D)J Recombination genetics
Autoantibodies genetics
Autoimmune Diseases genetics
B-Lymphocytes immunology
Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 180
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 32059783
- Full Text :
- https://doi.org/10.1016/j.cell.2020.01.029