Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

Mandeep Singh; Katherine J.L. Jackson; Jing J. Wang; Peter Schofield; Matt A. Field; David Koppstein; Timothy J. Peters; Deborah L. Burnett; Simone Rizzetto; Damien Nevoltris; Etienne Masle-Farquhar; Megan L. Faulks; Amanda Russell; Divya Gokal; Asami Hanioka; Keisuke Horikawa; Alexander D. Colella; Timothy K. Chataway; James Blackburn; Tim R. Mercer; David B. Langley; D. Margaret Goodall; Roy Jefferis; Muralikrishna Gangadharan Komala; Anthony D. Kelleher; Dan Suan; Maureen Rischmueller; Daniel Christ; Robert Brink; Fabio Luciani; Tom P. Gordon; Christopher C. Goodnow; Joanne H. Reed

doi:10.1016/j.cell.2020.01.029

Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

Mandeep Singh
, Katherine J.L. Jackson
, Jing J. Wang
, Peter Schofield
, Matt A. Field
, David Koppstein
, Timothy J. Peters
, Deborah L. Burnett
, Simone Rizzetto
, Damien Nevoltris
, Etienne Masle-Farquhar
, Megan L. Faulks
, Amanda Russell
, Divya Gokal
, Asami Hanioka
, Keisuke Horikawa
, Alexander D. Colella
, Timothy K. Chataway
, James Blackburn
, Tim R. Mercer

David B. Langley, D. Margaret Goodall, Roy Jefferis, Muralikrishna Gangadharan Komala, Anthony D. Kelleher, Dan Suan, Maureen Rischmueller, Daniel Christ, Robert Brink, Fabio Luciani, Tom P. Gordon, Christopher C. Goodnow^*, Joanne H. Reed

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

114 Citations (Scopus)

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.

Original language	English
Pages (from-to)	878-894.e19
Journal	Cell
Volume	180
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2020.01.029
Publication status	Published - 5 Mar 2020

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Singh, M., Jackson, K. J. L., 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., ... Reed, J. H. (2020). Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody. Cell, 180(5), 878-894.e19. https://doi.org/10.1016/j.cell.2020.01.029

@article{0e3fe92127014c90bf1dd296f279b085,

title = "Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody",

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",

author = "Mandeep Singh and Jackson, \{Katherine J.L.\} and Wang, \{Jing J.\} and Peter Schofield and Field, \{Matt A.\} and David Koppstein and Peters, \{Timothy J.\} and Burnett, \{Deborah L.\} and Simone Rizzetto and Damien Nevoltris and Etienne Masle-Farquhar and Faulks, \{Megan L.\} and Amanda Russell and Divya Gokal and Asami Hanioka and Keisuke Horikawa and Colella, \{Alexander D.\} and Chataway, \{Timothy K.\} and James Blackburn and Mercer, \{Tim R.\} and Langley, \{David B.\} and Goodall, \{D. Margaret\} and Roy Jefferis and \{Gangadharan Komala\}, Muralikrishna and Kelleher, \{Anthony D.\} and Dan Suan and Maureen Rischmueller and Daniel Christ and Robert Brink and Fabio Luciani and Gordon, \{Tom P.\} and Goodnow, \{Christopher C.\} and Reed, \{Joanne H.\}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = mar,

day = "5",

doi = "10.1016/j.cell.2020.01.029",

language = "English",

volume = "180",

pages = "878--894.e19",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

}

Singh, M, Jackson, KJL, Wang, JJ, Schofield, P, Field, MA, Koppstein, D, Peters, TJ, Burnett, DL, Rizzetto, S, Nevoltris, D, Masle-Farquhar, E, Faulks, ML, Russell, A, Gokal, D, Hanioka, A, Horikawa, K, Colella, AD, Chataway, TK, Blackburn, J, Mercer, TR, Langley, DB, Goodall, DM, Jefferis, R, Gangadharan Komala, M, Kelleher, AD, Suan, D, Rischmueller, M, Christ, D, Brink, R, Luciani, F, Gordon, TP, Goodnow, CC & Reed, JH 2020, 'Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody', Cell, vol. 180, no. 5, pp. 878-894.e19. https://doi.org/10.1016/j.cell.2020.01.029

TY - JOUR

T1 - Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

AU - Singh, Mandeep

AU - Jackson, Katherine J.L.

AU - Wang, Jing J.

AU - Schofield, Peter

AU - Field, Matt A.

AU - Koppstein, David

AU - Peters, Timothy J.

AU - Burnett, Deborah L.

AU - Rizzetto, Simone

AU - Nevoltris, Damien

AU - Masle-Farquhar, Etienne

AU - Faulks, Megan L.

AU - Russell, Amanda

AU - Gokal, Divya

AU - Hanioka, Asami

AU - Horikawa, Keisuke

AU - Colella, Alexander D.

AU - Chataway, Timothy K.

AU - Blackburn, James

AU - Mercer, Tim R.

AU - Langley, David B.

AU - Goodall, D. Margaret

AU - Jefferis, Roy

AU - Gangadharan Komala, Muralikrishna

AU - Kelleher, Anthony D.

AU - Suan, Dan

AU - Rischmueller, Maureen

AU - Christ, Daniel

AU - Brink, Robert

AU - Luciani, Fabio

AU - Gordon, Tom P.

AU - Goodnow, Christopher C.

AU - Reed, Joanne H.

PY - 2020/3/5

Y1 - 2020/3/5

N2 - 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.

AB - 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.

KW - autoantibody

KW - cryoglobulinemia

KW - lymphoma

KW - rheumatoid factor

KW - single cell omics

KW - somatic mutation

KW - vasculitis

UR - https://www.scopus.com/pages/publications/85080139890

U2 - 10.1016/j.cell.2020.01.029

DO - 10.1016/j.cell.2020.01.029

M3 - Article

SN - 0092-8674

VL - 180

SP - 878-894.e19

JO - Cell

JF - Cell

IS - 5

ER -

Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

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