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


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-Fc?R interactions. However, we and others have demonstrated that anti-GPIb? (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting Fc?R pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIb? and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIb?, 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-Fc?R-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIb?-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.

SUBMITTER: Li J 

PROVIDER: S-EPMC4518313 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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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  ...[more]

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