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

Authors :
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
Kuijpers TW
Whetton AD
Sickmann A
Freson K
Downes K
Erber WN
Frontini M
Nurden P
Ouwehand WH
Favier R
Guerrero JA
Source :
Blood [Blood] 2020 Oct 22; Vol. 136 (17), pp. 1956-1967.
Publication Year :
2020

Abstract

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.<br /> (© 2020 by The American Society of Hematology.)

Details

Language :
English
ISSN :
1528-0020
Volume :
136
Issue :
17
Database :
MEDLINE
Journal :
Blood
Publication Type :
Academic Journal
Accession number :
32693407
Full Text :
https://doi.org/10.1182/blood.2019004776