Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia

Nat Commun. 2015 Jul 17;6:7737. doi: 10.1038/ncomms8737.

Abstract

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc-FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell receptors, which is fundamentally different from the classical Fc-FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Murine-Derived / immunology*
  • Blood Platelets
  • Blotting, Western
  • Flow Cytometry
  • Hepatocytes / metabolism
  • Humans
  • Immunohistochemistry
  • Integrin beta3 / immunology*
  • Mice
  • Mice, Knockout
  • Neuraminidase / antagonists & inhibitors
  • Neuraminidase / immunology*
  • Platelet Glycoprotein GPIIb-IIIa Complex / immunology*
  • Platelet Glycoprotein GPIb-IX Complex / immunology*
  • Purpura, Thrombocytopenic, Idiopathic / immunology*

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Integrin beta3
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Platelet Glycoprotein GPIb-IX Complex
  • adhesion receptor
  • Neuraminidase