Dangerous liaisons: hemostatic proteins meet the immune system

The immune system can mount both adaptive and non-adaptive responses to neutralize and quickly eliminate incoming pathogens. Dysregulation of the immune response can result in auto-immunity; auto-immunity towards hemostatic proteins such as ADAMTS13 or other hemostatic proteins can result in either bleeding or thrombosis. The development of auto-antibodies to the VWF cleaving protease ADAMTS13 presents with a thrombotic micro-angiopathy that has been designated thrombotic thrombocytopenic purpura (TTP). In the absence of ADAMTS13, ultra-large VWF polymers originating from Weibel-Paalde bodies promote the formation of platelet-rich thrombi in the micro-circulation giving rise to hemolytic anemia and thrombocytopenia.

Several studies have shown that HLA-DRB1*11 is a risk factor for acquired TTP. We have pulsed dendritic cells derived of DRB1*11 positive and negative donors with purified ADAMTS13. Subsequently the HLA-DR presented peptide repertoire was interrogated for the presence of ADAMTS13 derived peptides. Remarkably, a single CUB2 domain derived peptides was found to be preferentially presented on HLA-DRB1*11. CD4+ T cells recognizing this petide were found to be present in patients with acquired TTP. Thess findings raise the possibility that functional presentation of CUB2 domain derived peptides contributes to the onset of acquired TTP in HLA-DRB1*11 positive patients. 

Allo-immune responses towards hemostatic or platelet or red blood cell expressed antigens are frequently observed in the context of cellular or protein replacement therapies. This is illustrated by the development of inhibitory antibodies that develop in 20-30% of the severe hemophilia A patients that are treated with factor VIII concentrates. The intrinsic immunogenicity of blood coagulation factor VIII is studied with emphasis on its binding and presentation by antigen presenting cells. 

Key publications

• Peyron, I., Hartholt, R. B., Pedro-Cos, L., van Alphen, F., Brinke, A. T., Lardy, N., Meijer, A. B., and Voorberg, J. (2018) Comparative profiling of HLA-DR and HLA-DQ associated factor VIII peptides presented by monocyte-derived dendritic cells. Haematologica 2018 Jan;103(1):172-178.
• Verbij, F. C., Sorvillo, N., Kaijen, P. H. P., Hrdinova, J., Peyron, I., Fijnheer, R., Ten Brinke, A., Meijer, A. B., van Alphen, F. P. J., van den Berg, T. K., Graversen, J. J. H., Moestrup, S. K., and Voorberg, J. (2017) The class I scavenger receptor CD163 promotes internalization of ADAMTS13 by macrophages. Blood Adv 2017 Jan 16;1(5):293-305.
• Verbij FC, Turksma AW, de Heij F, Kaijen P, Lardy N, Fijnheer R,  Sorvillo N, ten Brinke A, Voorberg J.  CD4+ T cells from patients with acquired thrombotic thrombocytopenic purpura recognize CUB-2 domain derived peptides. Blood. 2016 Mar 24;127(12):1606-9
• Sorvillo N, Hartholt RB, Bloem E, Sedek M, Ten BA, van der Zwaan C, van Alphen F, Meijer AB, Voorberg J. Von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII. Haematologica. 2016 Mar;101(3):309-18.
• Verbij FC, Stokhuijzen E, Kayen PH, van Alphen F, Meijer AB, Voorberg J. Identiifcation of glycans on plasma-derived ADAMTS13. Blood. 2016 Nov 24;128(21):e51-e58