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.
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Authors | June Li, Dianne E van der Wal, Guangheng Zhu, Miao Xu, Issaka Yougbare, Li Ma, Brian Vadasz, Naadiya Carrim, Renata Grozovsky, Min Ruan, Lingyan Zhu, Qingshu Zeng, Lili Tao, Zhi-min Zhai, Jun Peng, Ming Hou, Valery Leytin, John Freedman, Karin M Hoffmeister, Heyu Ni |
Journal | Nature communications
(Nat Commun)
Vol. 6
Pg. 7737
(Jul 17 2015)
ISSN: 2041-1723 [Electronic] England |
PMID | 26185093
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal, Murine-Derived
- Integrin beta3
- Platelet Glycoprotein GPIIb-IIIa Complex
- Platelet Glycoprotein GPIb-IX Complex
- adhesion receptor
- Neuraminidase
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Topics |
- 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, immunology)
- Platelet Glycoprotein GPIIb-IIIa Complex
(immunology)
- Platelet Glycoprotein GPIb-IX Complex
(immunology)
- Purpura, Thrombocytopenic, Idiopathic
(immunology)
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