Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
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Author
Li, June
van der Wal, Dianne E.
Zhu, Guangheng
Xu, Miao
Yougbare, Issaka
Ma, Li
Vadasz, Brian
Carrim, Naadiya
Grozovsky, Renata
Ruan, Min
Zhu, Lingyan
Zeng, Qingshu
Tao, Lili
Zhai, Zhi-min
Peng, Jun
Hou, Ming
Leytin, Valery
Freedman, John
Ni, Heyu
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ncomms8737Metadata
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Li, J., D. E. van der Wal, G. Zhu, M. Xu, I. Yougbare, L. Ma, B. Vadasz, et al. 2015. “Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.” Nature Communications 6 (1): 7737. doi:10.1038/ncomms8737. http://dx.doi.org/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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518313/pdf/Terms of Use
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