TY - JOUR
T1 - Neutrophil specific granule and NETosis defects in gray platelet syndrome
AU - Aarts, Cathelijn E. M.
AU - Downes, Kate
AU - Hoogendijk, Arie J.
AU - Sprenkeler, Evelien G. G.
AU - Gazendam, Roel P.
AU - Favier, Remi
AU - Favier, Marie
AU - Tool, Anton T. J.
AU - van Hamme, John L.
AU - Kostadima, Myrto A.
AU - Waller, Kate
AU - Zieger, Barbara
AU - van Bergen, Maaike G. J. M.
AU - Langemeijer, Saskia M. C.
AU - van der Reijden, Bert A.
AU - Janssen, Hans
AU - van den Berg, Timo K.
AU - van Bruggen, Robin
AU - Meijer, Alexander B.
AU - Ouwehand, Willem H.
AU - Kuijpers, Taco W.
N1 - Funding Information: The patients with GPS were enrolled in the National Institute for Health Research (NIHR) BioResource Rare Diseases and their DNA analyzed by the associated BRIDGE genome sequencing projects. Both initiatives are supported by the NIHR (http://www.nihr.ac.uk). Research in the Ouwehand laboratory is supported by grants from the European Commission, NIHR, and the British Heart Foundation (RP-PG-0310-1002 and RG/09/12/28096). The laboratory also receives funding from NHS Blood and Transplant. K.D. is funded as a Higher Specialist Scientist Training (HSST) trainee by Health Funding Information: Education England. R.P.G. was supported by the Landsteiner Foundation for Blood Transfusion Research (LSBR 1706) awarded to T.W.K. C.E.M. was supported by the Sanquin Blood Supply Product and Process Development Cellular Products Fund (PPOC 2089). Publisher Copyright: © 2021 by The American Society of Hematology.
PY - 2021/1/26
Y1 - 2021/1/26
N2 - Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by a lack of a-granules in platelets and progressive myelofibrosis. Rare loss-of-function variants in neurobeachin-like 2 (NBEAL2), a member of the family of beige and Chédiak-Higashi (BEACH) genes, are causal of GPS. It is suggested that BEACH domain containing proteins are involved in fusion, fission, and trafficking of vesicles and granules. Studies in knockout mice suggest that NBEAL2 may control the formation and retention of granules in neutrophils. We found that neutrophils obtained from the peripheral blood from 13 patients with GPS have a normal distribution of azurophilic granules but show a deficiency of specific granules (SGs), as confirmed by immunoelectron microscopy and mass spectrometry proteomics analyses. CD341 hematopoietic stem cells (HSCs) from patients with GPS differentiated into mature neutrophils also lacked NBEAL2 expression but showed similar SG protein expression as control cells. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as a potentially important regulator of granule release. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis, and killing of bacteria and fungi, were intact. NETosis was absent in circulating GPS neutrophils. Lack of NETosis is suggested to be independent of NBEAL2 expression but associated with SG defects instead, as indicated by comparison with HSC-derived neutrophils. Since patients with GPS do not excessively suffer from infections, the consequence of the reduced SG content and lack of NETosis for innate immunity remains to be explored.
AB - Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by a lack of a-granules in platelets and progressive myelofibrosis. Rare loss-of-function variants in neurobeachin-like 2 (NBEAL2), a member of the family of beige and Chédiak-Higashi (BEACH) genes, are causal of GPS. It is suggested that BEACH domain containing proteins are involved in fusion, fission, and trafficking of vesicles and granules. Studies in knockout mice suggest that NBEAL2 may control the formation and retention of granules in neutrophils. We found that neutrophils obtained from the peripheral blood from 13 patients with GPS have a normal distribution of azurophilic granules but show a deficiency of specific granules (SGs), as confirmed by immunoelectron microscopy and mass spectrometry proteomics analyses. CD341 hematopoietic stem cells (HSCs) from patients with GPS differentiated into mature neutrophils also lacked NBEAL2 expression but showed similar SG protein expression as control cells. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as a potentially important regulator of granule release. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis, and killing of bacteria and fungi, were intact. NETosis was absent in circulating GPS neutrophils. Lack of NETosis is suggested to be independent of NBEAL2 expression but associated with SG defects instead, as indicated by comparison with HSC-derived neutrophils. Since patients with GPS do not excessively suffer from infections, the consequence of the reduced SG content and lack of NETosis for innate immunity remains to be explored.
UR - http://www.scopus.com/inward/record.url?scp=85099805726&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/bloodadvances.2020002442
DO - https://doi.org/10.1182/bloodadvances.2020002442
M3 - Article
C2 - 33496751
SN - 2473-9529
VL - 5
SP - 549
EP - 564
JO - Blood advances
JF - Blood advances
IS - 2
ER -