Thesis Fabian Verbij

On 19 April 2017 (14:00 hrs) Fabian Verbij defended his thesis 'Immune recognition of ADAMTS13 in acquired TTP' at the University of Amsterdam.

Promotor: Prof JJ Voorberg PhD
Copromotor: R Fijnheer MD PhD and JA ten Brinke PhD 

Venue: Agnietenkapel, Oudezijds Voorburgwal 231, Amsterdam

Summary

Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic micro-angiopathy presenting with hemolytic anemia and thrombocytopenia that results from an acquired or congenital functional deficiency of the von Willebrand factor cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats member 13). Acquired TTP is due to the development of auto-antibodies directed towards ADAMTS13 in healthy individuals. It is currently not known what triggers the onset of acquired TTP in these individuals.

We found that macrophages efficiently endocytosed ADAMTS13 via the scavenger receptor CD163. CD163 is highly expressed on tissue-resident macrophages in the liver and the spleen, positioning it as a candidate receptor involved in clearance of ADAMTS13 from the circulation. We identified for the first time CD4+ reactive T-cells against ADAMTS13 and ADAMTS13-derived peptides in 2 patients with acquired TTP. Using a mass spectrometric approach we extended our knowledge on the ADAMTS13-derived peptides that are presented on MHC-II by monocyte derived dendritic cells. We developed a method that allows for monitoring of peptides presented on HLA-DQ and compared those peptides to the peptides presented on HLA-DR. These data provide a basis for more extensive profiling of CD4+ T-cells in patients with acquired TTP.

Our findings complement previous studies on the association of specific HLA-DR (DRB1*11) and HLA-DQ (DQB1*03) and the onset of acquired TTP. Since ADAMTS13 is highly glycosylated and glycosylation is reported to play an important role in the onset of several autoimmune diseases we mapped the glycan structures attached on ADAMTS13 using a mass spectrometry.