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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.
Highlights
Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex
To examine the effects of anti-GPIba and anti-GPIIbIIIa antibodies on platelet function and clearance, we utilized genedeficient ( À / À ) mice to generate a panel of mouse anti-mouseGPIba and -GPIIbIIIa monoclonal antibodies (mAbs), which possess cross-reactivity against other species, including tested human, rat and/or pig antigens (Table 1)
This is the first report that anti-GPIba antibodies can cross-react with GPIba from different species. Further characterization of these antibodies revealed that some of these mAbs affect ristocetin/botrocetin- or ADP/thrombin-induced platelet aggregation, which are mediated by GPIba[26] or GPIIbIIIa, respectively (Table 1)[27,28,29]
Summary
Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. We generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIba and GPIIbIIIa of different species Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIba, 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–FcgR-dependent macrophage phagocytosis. Sialidase inhibitors ameliorate anti-GPIba-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. Platelet destruction following autoantibody binding has generally been considered to occur in the spleen, through binding of the Fc portion of immunoglobulins on the platelet surface to FcgRIIa and FcgRIIIa on tissue macrophages of the reticuloendothelial system[2]
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