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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; Gangadharan Komala, Muralikrishna; Kelleher, Anthony D; Suan, Dan; Rischmueller, Maureen; Christ, Daniel; Brink, Robert; Luciani, Fabio; Gordon, Tom P; Goodnow, Christopher C; Reed, Joanne H.
Affiliation
  • Singh M; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Jackson KJL; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Wang JJ; Department of Immunology, Flinders University and SA Pathology, Bedford Park, SA 5042, Australia.
  • Schofield P; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Field MA; Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Smithfield, QLD 4878, Australia; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.
  • Koppstein D; Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Peters TJ; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Burnett DL; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Rizzetto S; Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Nevoltris D; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Masle-Farquhar E; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Faulks ML; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Russell A; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Gokal D; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Hanioka A; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia; Tokyo Medical and Dental University, Tokyo 113-851, Japan.
  • Horikawa K; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.
  • Colella AD; Department of Immunology, Flinders University and SA Pathology, Bedford Park, SA 5042, Australia; Flinders Proteomics Facility, Flinders University, Bedford Park, SA 5042, Australia.
  • Chataway TK; Flinders Proteomics Facility, Flinders University, Bedford Park, SA 5042, Australia.
  • Blackburn J; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Mercer TR; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA.
  • Langley DB; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
  • Goodall DM; Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
  • Jefferis R; Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
  • Gangadharan Komala M; Hawkesbury District Health Service and University of Sydney, Sydney, NSW 2777, Australia.
  • Kelleher AD; Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Suan D; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; Westmead Clinical School, The University of Sydney, Westmead, NSW 2145, Australia.
  • Rischmueller M; Rheumatology Department, The Queen Elizabeth Hospital and Discipline of Medicine, University of Adelaide, Woodville South, SA 5011, Australia.
  • Christ D; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Brink R; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Luciani F; Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW 2052, Australia; School of Medical Sciences and Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW 2052, Australia.
  • Gordon TP; Department of Immunology, Flinders University and SA Pathology, Bedford Park, SA 5042, Australia.
  • Goodnow CC; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Medical Sciences and Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW 2052, Australia. Electronic address: c.goodnow@garvan.org.au.
  • Reed JH; The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia. Electronic address: j.reed@garvan.org.au.
Cell ; 180(5): 878-894.e19, 2020 03 05.
Article in En | MEDLINE | ID: mdl-32059783
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autoantibodies / Autoimmune Diseases / B-Lymphocytes / Lymphoma Limits: Animals / Humans Language: En Journal: Cell Year: 2020 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autoantibodies / Autoimmune Diseases / B-Lymphocytes / Lymphoma Limits: Animals / Humans Language: En Journal: Cell Year: 2020 Document type: Article Affiliation country: