Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer.
Scleroderma is a chronic autoimmune rheumatic disease associated with widespread tissue fibrosis and vasculopathy. Approximately two-thirds of all patients with scleroderma present with three dominant autoantibody subsets. Here, we used a pair of complementary high-throughput methods for antibody epitope discovery to examine patients with scleroderma with or without known autoantibody specificities. We identified a specificity for the minor spliceosome complex containing RNA Binding Region (RNP1, RNA recognition motif) Containing 3 (RNPC3) that is found in patients with scleroderma without known specificities and is absent in unrelated autoimmune diseases. We found strong evidence for both intra- and intermolecular epitope spreading in patients with RNA polymerase III (POLR3) and the minor spliceosome specificities. Our results demonstrate the utility of these technologies in rapidly identifying antibodies that can serve as biomarkers of disease subsets in the evolving precision medicine era.
Program in Biophysics, Harvard University, Cambridge, MA 02115.|Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA 02139.|Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.|Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115.|Department of Genetics, Program in Virology, Harvard University Medical School, Boston, MA 02115.
George J
GJ
Xu
Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
Ami A
AA
Shah
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.|Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115.|Department of Genetics, Program in Virology, Harvard University Medical School, Boston, MA 02115.
Mamie Z
MZ
Li
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.|Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115.|Department of Genetics, Program in Virology, Harvard University Medical School, Boston, MA 02115.
Qikai
Q
Xu
Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
Antony
A
Rosen
Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224 selledge@genetics.med.harvard.edu lcr@jhmi.edu.
Livia
L
Casciola-Rosen
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115; selledge@genetics.med.harvard.edu lcr@jhmi.edu.|Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115.|Department of Genetics, Program in Virology, Harvard University Medical School, Boston, MA 02115.
Stephen J
SJ
Elledge
D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D061505:Cell Surface Display Techniques; D015897:Comorbidity; D000939:Epitopes / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016366:Open Reading Frames; D012320:RNA Polymerase III / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D012595:Scleroderma, Systemic / Q000097:blood / Q000276:immunology*; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D009687:Nuclear Proteins; C485562:PDCD7 protein, human; D016601:RNA-Binding Proteins; C498172:RNPC3 protein, human; D017411:Ribonucleoproteins, Small Nuclear; C552138:SNRNP25 protein, human; C552127:SNRNP35 protein, human; D014157:Transcription Factors; D012320:RNA Polymerase III
PLATO; PhIP-Seq; autoimmunity; systemic sclerosis