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Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome
BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604387/ https://www.ncbi.nlm.nih.gov/pubmed/31262358 http://dx.doi.org/10.1186/s13075-019-1947-2 |
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author | Barbati, C. Stefanini, L. Colasanti, T. Cipriano, E. Celia, A. Gabriele, G. Vomero, M. Ceccarelli, F. Spinelli, F. R. Finucci, A. Speziali, M. Orso, G. Margiotta, D. P. E. Conti, F. Violi, F. Afeltra, A. Valesini, G. Alessandri, C. |
author_facet | Barbati, C. Stefanini, L. Colasanti, T. Cipriano, E. Celia, A. Gabriele, G. Vomero, M. Ceccarelli, F. Spinelli, F. R. Finucci, A. Speziali, M. Orso, G. Margiotta, D. P. E. Conti, F. Violi, F. Afeltra, A. Valesini, G. Alessandri, C. |
author_sort | Barbati, C. |
collection | PubMed |
description | BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at − 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbβ3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS. |
format | Online Article Text |
id | pubmed-6604387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66043872019-07-12 Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome Barbati, C. Stefanini, L. Colasanti, T. Cipriano, E. Celia, A. Gabriele, G. Vomero, M. Ceccarelli, F. Spinelli, F. R. Finucci, A. Speziali, M. Orso, G. Margiotta, D. P. E. Conti, F. Violi, F. Afeltra, A. Valesini, G. Alessandri, C. Arthritis Res Ther Research Article BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at − 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbβ3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS. BioMed Central 2019-07-01 2019 /pmc/articles/PMC6604387/ /pubmed/31262358 http://dx.doi.org/10.1186/s13075-019-1947-2 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Barbati, C. Stefanini, L. Colasanti, T. Cipriano, E. Celia, A. Gabriele, G. Vomero, M. Ceccarelli, F. Spinelli, F. R. Finucci, A. Speziali, M. Orso, G. Margiotta, D. P. E. Conti, F. Violi, F. Afeltra, A. Valesini, G. Alessandri, C. Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
title | Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
title_full | Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
title_fullStr | Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
title_full_unstemmed | Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
title_short | Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
title_sort | anti-d4gdi antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604387/ https://www.ncbi.nlm.nih.gov/pubmed/31262358 http://dx.doi.org/10.1186/s13075-019-1947-2 |
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