Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by recurrent venous and/or arterial thrombosis or fetal loss associated with persistently elevated titers of antiphospholipid antibodies (aPLs). It has been known for over 20 years that aPL are causally involved in the pathogenesis of APS. However, the underlying signaling pathway is only partially understood.
I will focus on the characterization of the underlying cellular mechanisms. We could recently show that aPL activate an endosomal NADPH oxidase in different cell types. This increases the risk of thrombosis in patients. A detailed elucidation of the precise mechanisms by which aPL cause thrombosis promises a better understanding of APS pathogenesis and might provide new targets for the development of therapeutic strategies.
- Pathogenesis of Antiphospholipid Syndrome
- Activation and assembly of endosomal NADPH oxidase
- Role of endosmal NADPH oxidase in innate immunity
- Translocation of intracellular toll-like receptors
- Antonia Köhler (Master Student)
- Antje Canisius (MTA)
- Carolin Orning (MTA)
Mentor of the Virchow-Fellow is Professor Karl J. Lackner, MD, Director of the Institute of Clinical Chemistry and Laboratory Medicine.
Bachelor of Science “Molecular Biology”, University of Mainz
Internship at Life & Brain GmbH, Bonn
Master of Science “Biomedicine”, University of Mainz
Internship at Sanofi-Aventis Deutschland GmbH, Science and Medical Affairs, Frankfurt am Main
Promotion: “Signaling transduction of IgG Antiphospholipid antibodies in Plasmacytoid dendritic cells and MonoMac-1 cells” at the Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Prof. Dr. Karl J. Lackner
Research Associate of the Institute of Clinical Chemistry and Laboratory Medicine
- Lackner KJ, Manukyan D, Müller-Calleja N (2017) Pathophysiological insights into the antiphospholipid syndrome. Hamostaseologie 37: 202-207
- Manukyan D, Müller-Calleja N, Jäckel S, Luchmann K, Monnikes R, Kiouptsi K, Reinhardt C, Jurk K, Walter U, Lackner KJ. Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice. Journal of thrombosis and haemostasis 14:1011-1020. 2016.
- Müller-Calleja N, Kohler A, Siebald B, Canisius A, Orning C, Radsak M, Stein P, Monnikes R, Lackner KJ. Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome. Thrombosis and haemostasis 113:1071-1083, 2015.
- Prinz N, Clemens N, Canisius A, Lackner KJ: Endosomal NADPH-Oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells - lessons from the antiphospholipid syndrome. Thrombosis and Haemostasis. 2013 Mar 5;109(3):525-31.
- Gladigau G, Haselmayer P, Scharrer I, Munder M, Prinz N, Lackner K, Schild H, Stein P, Radsak MP: a role for Toll-like receptor mediated signals in neutrophils in the pathogenesis of the anti-phospholipid syndrome. PLoS One. 2012;7(7):e42176. Epub 2012 Jul 31.
- Prinz N, Clemens N, Strand D, Pütz I, Lorenz M, Daiber A, Stein P, Degreif A, Rad- sak M, Schild H, Bauer S, von Landenberg P, Lackner KJ: Antiphospholipid antibod- ies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood. 2011 Aug 25;118(8):2322-32.
- Prinz N, Häuser F, Lorenz M, Lackner KJ, von Landenberg P: Structural and func- tional characterization of a human IgG monoclonal antiphospholipid antibody. Im- munobiology. 2011 Jan-Feb;216(1-2):145-51.
- Hurst J, Lorenz M, Prinz N, von Landenberg P: The roll of Toll-like receptors in the antiphospholipid syndrome. Curr Rheumatol Rep. 2010 Feb;12(1):58-63. Review.
- Döring Y, Hurst J, Lorenz M, Prinz N, Clemens N, Drechsler MD, Bauer S, Chapman J, Shoenfeld Y, Blank M, Lackner KJ, von Landenberg P: Human antiphospholipid antibodies induce TNFalpha in monocytes via Toll-like receptor 8. Immunobiology. 2010 Mar;215(3):230-41.
- Hurst J*, Prinz N*, Lorenz M, Bauer S, Chapman J, Lackner KJ, von Landenberg P: TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1beta and caspase-1 in monocytes and dendritic cells. Immunobi- ology. 2009;214(8):683-91. *Equal contribution