Preferential HLA-DRB1*11-dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

Blood. 2013 Apr 25;121(17):3502-10. doi: 10.1182/blood-2012-09-456780. Epub 2013 Jan 31.

Abstract

Autoantibodies directed against ADAMTS13 prohibit the processing of von Willebrand factor multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-derived peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11-positive and -negative donors were pulsed with ADAMTS13, and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations, HLA-DRB1*11- or DRB1*03-positive donors presented a limited number of CUB2-derived peptides. Pulsing of dendritic cells using higher concentrations of ADAMTS13 resulted in the presentation of larger numbers of ADAMTS13-derived peptides by both HLA-DRB1*11-positive and -negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide profiles revealed that CUB2 domain-derived peptides were presented with a higher efficiency when compared with other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13-present derivatives of a single CUB2-derived peptide. We hypothesize that functional presentation of CUB2-derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low-affinity, self-reactive CD4+ T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / immunology*
  • ADAM Proteins / metabolism
  • ADAMTS13 Protein
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Endocytosis
  • Flow Cytometry
  • HLA-DRB1 Chains / immunology*
  • HLA-DRB1 Chains / metabolism
  • Humans
  • Monocytes / cytology
  • Monocytes / immunology
  • Monocytes / metabolism
  • Peptide Fragments / immunology*
  • Peptide Fragments / metabolism
  • Purpura, Thrombotic Thrombocytopenic / etiology*
  • Purpura, Thrombotic Thrombocytopenic / pathology
  • Serine Endopeptidases / immunology
  • Serine Endopeptidases / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • HLA-DRB1 Chains
  • Peptide Fragments
  • CUB-serine protease, Panulirus argus
  • Serine Endopeptidases
  • ADAM Proteins
  • ADAMTS13 Protein
  • ADAMTS13 protein, human

Supplementary concepts

  • Thrombotic thrombocytopenic purpura, acquired