Targeting of platelet integrin alphaIIbbeta3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcgammaR.
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 GPIbalpha and integrin alpha(IIb)beta(3) were highly pathogenic, and mediated their effects via different Fc-dependent (alpha(IIb)beta(3)) and Fc-independent (GPIbalpha) 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(IIb)beta(3) results in acute systemic reaction and bleeding that is regulated by activating IgG Fc receptors (FcgammaR) and the inhibitory FcgammaRII. As shown by electron microscopy, anti-alpha(IIb)beta(3) IgG mediated initial loss of alpha(IIb)beta(3) integrin from platelet surfaces followed by rapid accumulation of alpha(IIb)beta(3) antibody-containing immune complex (IC)-like structures in spleen and liver in vivo. In FcRgamma chain deficiency, mice resisted bleeding, but not platelet destruction, while genetic ablation of FcgammaRII resulted in uncontrolled systemic reaction and severe hemorrhage leading to enhanced mortality. Together, these results provide evidence that IC formation and engagement of FcgammaR on effector cells determines the alpha(IIb)beta(3)-specific part of the platelet pathology of the systemic reaction and bleeding in murine thrombocytopenia.
Nieswandt
Bernhard
B
Department of Vascular Biology, Rudolf-Virchow-Zentrum, Universität Würzburg, 97078 Würzburg, Germany.
Bergmeier
Wolfgang
W
Schulte
Valerie
V
Takai
Toshiyuki
T
Baumann
Ulrich
U
Schmidt
Reinhold E
RE
Zirngibl
Hubert
H
Bloch
Wilhelm
W
Gessner
J Engelbert
JE
D000818:Animals; D051379:Mice; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D013921:Thrombocytopenia / Q000503:physiopathology*
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017452:Receptors, IgG