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Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

Johana Hrdinová1, Fabian C Verbij1, Paul H P Kaijen1

  • 1Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, the Netherlands.

Haematologica
|March 24, 2018
PubMed

Insights

Researchers identified specific ADAMTS13 protein fragments presented by HLA-DQ molecules, offering new insights into acquired thrombotic thrombocytopenic purpura (TTP) pathogenesis. This study maps TTP-associated ADAMTS13 epitopes, crucial for understanding TTP development.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by microthrombi formation due to autoantibodies against ADAMTS13, leading to insufficient processing of ultra-large von Willebrand factor multimers.
  • Major histocompatibility complex (MHC) class II alleles, including HLA-DRB1*11, HLA-DQB1*03, and HLA-DQB1*02:02, are identified risk factors for TTP development.
  • Previous work identified ADAMTS13 CUB2 domain peptides presented on HLA-DRB1*11 and HLA-DRB1*03, but the repertoire presented on HLA-DQ remained largely uncharacterized.

Purpose of the Study:

  • To characterize the repertoire of ADAMTS13-derived peptides presented on HLA-DQ molecules.
  • To further investigate ADAMTS13 peptides presented on HLA-DR molecules.
  • To identify potential T-cell epitopes involved in the pathogenesis of acquired TTP.

Main Methods:

  • Purification of HLA/peptide complexes from ADAMTS13-pulsed monocyte-derived dendritic cells using HLA-DR- and HLA-DQ-specific antibodies.
  • Identification of eluted ADAMTS13-derived peptides using mass spectrometry.
  • In silico analysis of identified peptides for potential T-cell responses using EpiMatrix and JanusMatrix tools.

Main Results:

  • ADAMTS13-derived peptides were identified on HLA-DR in all 9 samples and on HLA-DQ in 4 out of 9 samples.
  • Previously identified CUB2 domain peptides (FINVAPHAR and LIRDTHSLR) were confirmed on HLA-DR.
  • A total of 12 unique core-peptide sequences were identified on HLA-DR and 8 on HLA-DQ, including 4 novel core-peptides exclusively found on HLA-DQ.

Conclusions:

  • This study elucidates the repertoire of ADAMTS13 peptides presented by HLA-DQ molecules, expanding our understanding of TTP immunopathogenesis.
  • The identification of novel HLA-DQ-presented ADAMTS13 epitopes provides a basis for further investigation into TTP-specific T-cell responses.
  • These findings contribute to identifying immuno-dominant epitopes on ADAMTS13, crucial for understanding the mechanisms underlying acquired TTP.

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