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International Immunology, Vol. 15, No. 3, pp. 341-349, March 2003
© 2003 Japanese Society for Immunology

Targeting of platelet integrin {alpha}IIbß3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory Fc{gamma}R

Bernhard Nieswandt1, Wolfgang Bergmeier1, Valerie Schulte1, Toshiyuki Takai2, Ulrich Baumann4, Reinhold E. Schmidt4, Hubert Zirngibl1, Wilhelm Bloch3 and J. Engelbert Gessner4

1 Department of Vascular Biology, Rudolf-Virchow-Zentrum, Universität Würzburg, 97078 Würzburg, Germany 2 Department of Experimental Immunology, Tohoku University, and CREST Program of JST, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-8575, Japan 3 Institute I of Anatomy, University of Cologne, 50931 Cologne, Germany 4 Department of Clinical Immunology, Hannover Medical School, 30625 Hannover, Germany

Correspondence to: J. E. Gessner; E-mail: gessner.johannes{at}mh-hannover.de
Transmitting editor: S. Izui

Previous work on cellular destruction induced by several clinically relevant anti-platelet IgG antibodies suggested antigen-specific mechanisms in the development of immune thrombocytopenia in mice. mAb directed against mouse platelet GPIb{alpha} and integrin {alpha}IIbß3 were highly pathogenic, and mediated their effects via different Fc-dependent ({alpha}IIbß3) and Fc-independent (GPIb{alpha}) pathways, indicating that clearance of IgG-bound platelets is only one event in the pathogenesis of murine thrombocytopenia. Here, we demonstrate that in addition to thrombocytopenia, targeting of platelet integrin {alpha}IIbß3 results in acute systemic reaction and bleeding that is regulated by activating IgG Fc receptors (Fc{gamma}R) and the inhibitory Fc{gamma}RII. As shown by electron microscopy, anti-{alpha}IIbß3 IgG mediated initial loss of {alpha}IIbß3 integrin from platelet surfaces followed by rapid accumulation of {alpha}IIbß3 antibody-containing immune complex (IC)-like structures in spleen and liver in vivo. In FcR{gamma} chain deficiency, mice resisted bleeding, but not platelet destruction, while genetic ablation of Fc{gamma}RII resulted in uncontrolled systemic reaction and severe hemorrhage leading to enhanced mortality. Together, these results provide evidence that IC formation and engagement of Fc{gamma}R on effector cells determines the {alpha}IIbß3-specific part of the platelet pathology of the systemic reaction and bleeding in murine thrombocytopenia.

Keywords: {alpha}IIbß3 integrin, antibody, Fc{gamma} receptor, mouse, platelet


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