Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
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 o...
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Nature Pub. Group
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518313/ |
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pubmed-45183132015-08-07 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia 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 Hoffmeister, Karin M. Ni, Heyu Article 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. Nature Pub. Group 2015-07-17 /pmc/articles/PMC4518313/ /pubmed/26185093 http://dx.doi.org/10.1038/ncomms8737 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| 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 Hoffmeister, Karin M. Ni, Heyu |
| spellingShingle |
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 Hoffmeister, Karin M. Ni, Heyu Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| author_facet |
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 Hoffmeister, Karin M. Ni, Heyu |
| author_sort |
Li, June |
| title |
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| title_short |
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| title_full |
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| title_fullStr |
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| title_full_unstemmed |
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| title_sort |
desialylation is a mechanism of fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia |
| description |
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. |
| publisher |
Nature Pub. Group |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518313/ |
| _version_ |
1613253378253520896 |