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Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

2020Journal article Open access
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dc.contributor.authorSims, Matthew C
dc.contributor.authorMayer, Louisa
dc.contributor.authorCollins, Janine H
dc.contributor.authorBariana, Tadbir K
dc.contributor.authorMegy, Karyn
dc.contributor.authorLavenu-Bombled, Cecile
dc.contributor.authorSeyres, Denis
dc.contributor.authorKollipara, Laxmikanth
dc.contributor.authorBurden, Frances S
dc.contributor.authorGreene, Daniel
dc.contributor.authorLee, Dave
dc.contributor.authorRodriguez-Romera, Antonio
dc.contributor.authorAlessi, Marie-Christine
dc.contributor.authorAstle, William J
dc.contributor.authorBahou, Wadie F
dc.contributor.authorBury, Loredana
dc.contributor.authorChalmers, Elizabeth
dc.contributor.authorDa Silva, Rachael
dc.contributor.authorDe Candia, Erica
dc.contributor.authorDeevi, Sri V V
dc.contributor.authorFarrow, Samantha
dc.contributor.authorGomez, Keith
dc.contributor.authorGrassi, Luigi
dc.contributor.authorGreinacher, Andreas
dc.contributor.authorGresele, Paolo
dc.contributor.authorHart, Dan
dc.contributor.authorHurtaud, Marie-Françoise
dc.contributor.authorKelly, Anne M
dc.contributor.authorKerr, Ron
dc.contributor.authorLe Quellec, Sandra
dc.contributor.authorLeblanc, Thierry
dc.contributor.authorLeinøe, Eva B
dc.contributor.authorMapeta, Rutendo
dc.contributor.authorMcKinney, Harriet
dc.contributor.authorMichelson, Alan D
dc.contributor.authorMorais, Sara
dc.contributor.authorNugent, Diane
dc.contributor.authorPapadia, Sofia
dc.contributor.authorPark, Soo J
dc.contributor.authorPasi, John
dc.contributor.authorPodda, Gian Marco
dc.contributor.authorPoon, Man-Chiu
dc.contributor.authorReed, Rachel
dc.contributor.authorSekhar, Mallika
dc.contributor.authorShalev, Hanna
dc.contributor.authorSivapalaratnam, Suthesh
dc.contributor.authorSteinberg-Shemer, Orna
dc.contributor.authorStephens, Jonathan C
dc.contributor.authorTait, Robert C
dc.contributor.authorTurro, Ernest
dc.contributor.authorWu, John K M
dc.contributor.authorZieger, Barbara
dc.contributor.authorKuijpers, Taco W
dc.contributor.authorWhetton, Anthony D
dc.contributor.authorSickmann, Albert
dc.contributor.authorFreson, Kathleen
dc.contributor.authorDownes, Kate
dc.contributor.authorErber, Wendy N
dc.contributor.authorFrontini, Mattia
dc.contributor.authorNurden, Paquita
dc.contributor.authorOuwehand, Willem H
dc.contributor.authorFavier, Remi
dc.contributor.authorGuerrero, Jose A
dc.date.accessioned2021-07-09T10:30:40Z
dc.date.available2021-07-09T10:30:40Z
dc.date.issued2020
dc.description.abstractGray 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSims 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.pt_PT
dc.identifier.doi10.1182/blood.2019004776pt_PT
dc.identifier.issn1528-0020
dc.identifier.urihttp://hdl.handle.net/10400.16/2491
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherGrune & Strattonpt_PT
dc.relation.publisherversionhttps://ashpublications.org/blood/article/136/17/1956/461431/Novel-manifestations-of-immune-dysregulation-andpt_PT
dc.titleNovel manifestations of immune dysregulation and granule defects in gray platelet syndromept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.endPage1967pt_PT
oaire.citation.issue17pt_PT
oaire.citation.startPage1956pt_PT
oaire.citation.titleBloodpt_PT
oaire.citation.volume136pt_PT
person.familyNameMorais
person.givenNameSara
person.identifier.orcid0000-0003-4266-4457
person.identifier.scopus-author-id7007053742
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationda1ff44c-9f35-4590-a71d-9efc23ca038b
relation.isAuthorOfPublication.latestForDiscoveryda1ff44c-9f35-4590-a71d-9efc23ca038b

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