Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
van der Wal, Dianne E.
Ni, HeyuNote: Order does not necessarily reflect citation order of authors.
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CitationLi, 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.
AbstractImmune 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:21462074
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