Preferential HLA-DRB1*11-dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells.
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.
Department of Plasma Proteins, Sanquin Research, Plesmanlaan 125, Amsterdam, the Netherlands.
Nicoletta
N
Sorvillo
Simon D
SD
van Haren
Paul H
PH
Kaijen
Anja
A
ten Brinke
Rob
R
Fijnheer
Alexander B
AB
Meijer
Jan
J
Voorberg
D051722:ADAM Proteins / Q000276:immunology* / Q000378:metabolism; D000071120:ADAMTS13 Protein; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis; D005434:Flow Cytometry; D059811:HLA-DRB1 Chains / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011697:Purpura, Thrombotic Thrombocytopenic / Q000209:etiology* / Q000473:pathology; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D059811:HLA-DRB1 Chains; D010446:Peptide Fragments; C445579:CUB-serine protease, Panulirus argus; D012697:Serine Endopeptidases; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human