Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer

Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7526-E7534. doi: 10.1073/pnas.1615990113. Epub 2016 Nov 7.

Abstract

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.

Keywords: PLATO; PhIP-Seq; autoimmunity; systemic sclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Autoantibodies / blood*
  • Autoantigens / chemistry
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Cell Surface Display Techniques
  • Comorbidity
  • Epitopes / genetics
  • Humans
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Open Reading Frames
  • RNA Polymerase III / chemistry
  • RNA Polymerase III / genetics
  • RNA Polymerase III / immunology
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • Ribonucleoproteins, Small Nuclear / chemistry
  • Ribonucleoproteins, Small Nuclear / genetics
  • Ribonucleoproteins, Small Nuclear / immunology
  • Scleroderma, Systemic / blood
  • Scleroderma, Systemic / immunology*
  • Sequence Analysis, DNA
  • Skin Neoplasms / blood
  • Skin Neoplasms / immunology*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / immunology

Substances

  • Apoptosis Regulatory Proteins
  • Autoantibodies
  • Autoantigens
  • Epitopes
  • Nuclear Proteins
  • PDCD7 protein, human
  • RNA-Binding Proteins
  • RNPC3 protein, human
  • Ribonucleoproteins, Small Nuclear
  • SNRNP25 protein, human
  • SNRNP35 protein, human
  • Transcription Factors
  • RNA Polymerase III