Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome
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Publication Date: | 2020 |
Other Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/10400.16/2491 |
Summary: | Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease. |
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Novel manifestations of immune dysregulation and granule defects in gray platelet syndromeGray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.Grune & StrattonRepositório Científico do Centro Hospitalar Universitário de Santo AntónioSims, Matthew CMayer, LouisaCollins, Janine HBariana, Tadbir KMegy, KarynLavenu-Bombled, CecileSeyres, DenisKollipara, LaxmikanthBurden, Frances SGreene, DanielLee, DaveRodriguez-Romera, AntonioAlessi, Marie-ChristineAstle, William JBahou, Wadie FBury, LoredanaChalmers, ElizabethDa Silva, RachaelDe Candia, EricaDeevi, Sri V VFarrow, SamanthaGomez, KeithGrassi, LuigiGreinacher, AndreasGresele, PaoloHart, DanHurtaud, Marie-FrançoiseKelly, Anne MKerr, RonLe Quellec, SandraLeblanc, ThierryLeinøe, Eva BMapeta, RutendoMcKinney, HarrietMichelson, Alan DMorais, SaraNugent, DianePapadia, SofiaPark, Soo JPasi, JohnPodda, Gian MarcoPoon, Man-ChiuReed, RachelSekhar, MallikaShalev, HannaSivapalaratnam, SutheshSteinberg-Shemer, OrnaStephens, Jonathan CTait, Robert CTurro, ErnestWu, John K MZieger, BarbaraKuijpers, Taco WWhetton, Anthony DSickmann, AlbertFreson, KathleenDownes, KateErber, Wendy NFrontini, MattiaNurden, PaquitaOuwehand, Willem HFavier, RemiGuerrero, Jose A2021-07-09T10:30:40Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2491engSims MC, Mayer L, Collins JH, Bariana TK, Megy K, Lavenu-Bombled C, Seyres D, Kollipara L, Burden FS, Greene D, Lee D, Rodriguez-Romera A, Alessi MC, Astle WJ, Bahou WF, Bury L, Chalmers E, Da Silva R, De Candia E, Deevi SVV, Farrow S, Gomez K, Grassi L, Greinacher A, Gresele P, Hart D, Hurtaud MF, Kelly AM, Kerr R, Le Quellec S, Leblanc T, Leinøe EB, Mapeta R, McKinney H, Michelson AD, Morais S, Nugent D, Papadia S, Park SJ, Pasi J, Podda GM, Poon MC, Reed R, Sekhar M, Shalev H, Sivapalaratnam S, Steinberg-Shemer O, Stephens JC, Tait RC, Turro E, Wu JKM, Zieger B; NIHR BioResource, Kuijpers TW, Whetton AD, Sickmann A, Freson K, Downes K, Erber WN, Frontini M, Nurden P, Ouwehand WH, Favier R, Guerrero JA. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood. 2020 Oct 22;136(17):1956-1967. doi: 10.1182/blood.2019004776. PMID: 32693407; PMCID: PMC7582559.1528-002010.1182/blood.2019004776info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-20T11:00:54Zoai:repositorio.chporto.pt:10400.16/2491Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:38:42.320866Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
title |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
spellingShingle |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome Sims, Matthew C |
title_short |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
title_full |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
title_fullStr |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
title_full_unstemmed |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
title_sort |
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
author |
Sims, Matthew C |
author_facet |
Sims, Matthew C Mayer, Louisa Collins, Janine H Bariana, Tadbir K Megy, Karyn Lavenu-Bombled, Cecile Seyres, Denis Kollipara, Laxmikanth Burden, Frances S Greene, Daniel Lee, Dave Rodriguez-Romera, Antonio Alessi, Marie-Christine Astle, William J Bahou, Wadie F Bury, Loredana Chalmers, Elizabeth Da Silva, Rachael De Candia, Erica Deevi, Sri V V Farrow, Samantha Gomez, Keith Grassi, Luigi Greinacher, Andreas Gresele, Paolo Hart, Dan Hurtaud, Marie-Françoise Kelly, Anne M Kerr, Ron Le Quellec, Sandra Leblanc, Thierry Leinøe, Eva B Mapeta, Rutendo McKinney, Harriet Michelson, Alan D Morais, Sara Nugent, Diane Papadia, Sofia Park, Soo J Pasi, John Podda, Gian Marco Poon, Man-Chiu Reed, Rachel Sekhar, Mallika Shalev, Hanna Sivapalaratnam, Suthesh Steinberg-Shemer, Orna Stephens, Jonathan C Tait, Robert C Turro, Ernest Wu, John K M Zieger, Barbara Kuijpers, Taco W Whetton, Anthony D Sickmann, Albert Freson, Kathleen Downes, Kate Erber, Wendy N Frontini, Mattia Nurden, Paquita Ouwehand, Willem H Favier, Remi Guerrero, Jose A |
author_role |
author |
author2 |
Mayer, Louisa Collins, Janine H Bariana, Tadbir K Megy, Karyn Lavenu-Bombled, Cecile Seyres, Denis Kollipara, Laxmikanth Burden, Frances S Greene, Daniel Lee, Dave Rodriguez-Romera, Antonio Alessi, Marie-Christine Astle, William J Bahou, Wadie F Bury, Loredana Chalmers, Elizabeth Da Silva, Rachael De Candia, Erica Deevi, Sri V V Farrow, Samantha Gomez, Keith Grassi, Luigi Greinacher, Andreas Gresele, Paolo Hart, Dan Hurtaud, Marie-Françoise Kelly, Anne M Kerr, Ron Le Quellec, Sandra Leblanc, Thierry Leinøe, Eva B Mapeta, Rutendo McKinney, Harriet Michelson, Alan D Morais, Sara Nugent, Diane Papadia, Sofia Park, Soo J Pasi, John Podda, Gian Marco Poon, Man-Chiu Reed, Rachel Sekhar, Mallika Shalev, Hanna Sivapalaratnam, Suthesh Steinberg-Shemer, Orna Stephens, Jonathan C Tait, Robert C Turro, Ernest Wu, John K M Zieger, Barbara Kuijpers, Taco W Whetton, Anthony D Sickmann, Albert Freson, Kathleen Downes, Kate Erber, Wendy N Frontini, Mattia Nurden, Paquita Ouwehand, Willem H Favier, Remi Guerrero, Jose A |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Centro Hospitalar Universitário de Santo António |
dc.contributor.author.fl_str_mv |
Sims, Matthew C Mayer, Louisa Collins, Janine H Bariana, Tadbir K Megy, Karyn Lavenu-Bombled, Cecile Seyres, Denis Kollipara, Laxmikanth Burden, Frances S Greene, Daniel Lee, Dave Rodriguez-Romera, Antonio Alessi, Marie-Christine Astle, William J Bahou, Wadie F Bury, Loredana Chalmers, Elizabeth Da Silva, Rachael De Candia, Erica Deevi, Sri V V Farrow, Samantha Gomez, Keith Grassi, Luigi Greinacher, Andreas Gresele, Paolo Hart, Dan Hurtaud, Marie-Françoise Kelly, Anne M Kerr, Ron Le Quellec, Sandra Leblanc, Thierry Leinøe, Eva B Mapeta, Rutendo McKinney, Harriet Michelson, Alan D Morais, Sara Nugent, Diane Papadia, Sofia Park, Soo J Pasi, John Podda, Gian Marco Poon, Man-Chiu Reed, Rachel Sekhar, Mallika Shalev, Hanna Sivapalaratnam, Suthesh Steinberg-Shemer, Orna Stephens, Jonathan C Tait, Robert C Turro, Ernest Wu, John K M Zieger, Barbara Kuijpers, Taco W Whetton, Anthony D Sickmann, Albert Freson, Kathleen Downes, Kate Erber, Wendy N Frontini, Mattia Nurden, Paquita Ouwehand, Willem H Favier, Remi Guerrero, Jose A |
description |
Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-07-09T10:30:40Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.16/2491 |
url |
http://hdl.handle.net/10400.16/2491 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Sims MC, Mayer L, Collins JH, Bariana TK, Megy K, Lavenu-Bombled C, Seyres D, Kollipara L, Burden FS, Greene D, Lee D, Rodriguez-Romera A, Alessi MC, Astle WJ, Bahou WF, Bury L, Chalmers E, Da Silva R, De Candia E, Deevi SVV, Farrow S, Gomez K, Grassi L, Greinacher A, Gresele P, Hart D, Hurtaud MF, Kelly AM, Kerr R, Le Quellec S, Leblanc T, Leinøe EB, Mapeta R, McKinney H, Michelson AD, Morais S, Nugent D, Papadia S, Park SJ, Pasi J, Podda GM, Poon MC, Reed R, Sekhar M, Shalev H, Sivapalaratnam S, Steinberg-Shemer O, Stephens JC, Tait RC, Turro E, Wu JKM, Zieger B; NIHR BioResource, Kuijpers TW, Whetton AD, Sickmann A, Freson K, Downes K, Erber WN, Frontini M, Nurden P, Ouwehand WH, Favier R, Guerrero JA. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood. 2020 Oct 22;136(17):1956-1967. doi: 10.1182/blood.2019004776. PMID: 32693407; PMCID: PMC7582559. 1528-0020 10.1182/blood.2019004776 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Grune & Stratton |
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Grune & Stratton |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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