Targeting of platelet integrin αIIbβ3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcγR

Bernhard Nieswandt, Wolfgang Bergmeier, Valerie Schulte, Toshiyuki Takai, Ulrich Baumann, Reinhold E. Schmidt, Hubert Zirngibl, Wilhelm Bloch, J. Engelbert Gessner

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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 GPIbα and integrin αIIbβ3 were highly pathogenic, and mediated their effects via different Fc-dependent (αIIbβ3) and Fc-independent (GPIbα) 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 αIIbβ3 results in acute systemic reaction and bleeding that is regulated by activating IgG Fc receptors (FcγR) and the inhibitory FcγRII. As shown by electron microscopy, anti-αIIbβ3 IgG mediated initial loss of αIIbβ3 integrin from platelet surfaces followed by rapid accumulation of αIIbβ3 antibody-containing immune complex (IC)-like structures in spleen and liver in vivo. In FcRγ chain deficiency, mice resisted bleeding, but not platelet destruction, while genetic ablation of FcγRII resulted in uncontrolled systemic reaction and severe hemorrhage leading to enhanced mortality. Together, these results provide evidence that IC formation and engagement of FcγR on effector cells determines the αIIbβ3-specific part of the platelet pathology of the systemic reaction and bleeding in murine thrombocytopenia.

Original languageEnglish
Pages (from-to)341-349
Number of pages9
JournalInternational immunology
Volume15
Issue number3
DOIs
Publication statusPublished - 2003 Mar 1

Keywords

  • Antibody
  • Fcγ receptor
  • Mouse
  • Platelet
  • αβ integrin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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