TY - JOUR
T1 - Storage-induced platelet apoptosis is a potential risk factor for alloimmunization upon platelet transfusion
AU - Saris, Anno
AU - Peyron, Ivan
AU - van der Meer, Pieter F.
AU - Stuge, Tor B.
AU - Zwaginga, Jaap Jan
AU - van Ham, S. Marieke
AU - ten Brinke, Anja
PY - 2018/6/5
Y1 - 2018/6/5
N2 - Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency of alloimmunization after platelet transfusion, thereby showing the importance of white blood cells (WBCs) in inducing this alloresponse. It is, however, unknown if the residual risk for alloimmunization is caused by WBCs remaining after leukoreduction or if alloimmunization can be induced by platelets themselves. This study investigated the capacity of platelets to induce alloimmunization and identified potential product-related risk factors for alloimmunization. First, internalization of allogeneic platelets by dendritic cells (DCs) was demonstrated by confocal microscopy. Second, after internalization, presentation of platelet-derived peptides was shown by mass spectrometry analysis of human leukocytes antigen (HLA)-DR eluted peptides. Third, platelet-loaded DCs induced platelet-specific CD4 T cell responses. Altogether, this indicates a platelet-specific ability to induce alloimmunization. Therefore, factors enhancing platelet internalization may be identified as risk factor for alloimmunization by platelet concentrates. To investigate if storage of platelets is such a risk factor, internalization of stored platelets was compared with fresh platelets and showed enhanced internalization of stored platelets. Storage-induced apoptosis and accompanied phosphatidylserine exposure seemed to be instrumental for this. Indeed, DCs pre-incubated with apoptotic platelets induced the strongest IFN-γ production by CD4 T cells compared with pre-incubation with untreated or activated platelets. In conclusion, this study shows the capacity of platelets to induce platelet-specific alloimmune responses. Furthermore, storage-induced apoptosis of platelets is identified as potential risk factor for alloimmunization after platelet transfusions.
AB - Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency of alloimmunization after platelet transfusion, thereby showing the importance of white blood cells (WBCs) in inducing this alloresponse. It is, however, unknown if the residual risk for alloimmunization is caused by WBCs remaining after leukoreduction or if alloimmunization can be induced by platelets themselves. This study investigated the capacity of platelets to induce alloimmunization and identified potential product-related risk factors for alloimmunization. First, internalization of allogeneic platelets by dendritic cells (DCs) was demonstrated by confocal microscopy. Second, after internalization, presentation of platelet-derived peptides was shown by mass spectrometry analysis of human leukocytes antigen (HLA)-DR eluted peptides. Third, platelet-loaded DCs induced platelet-specific CD4 T cell responses. Altogether, this indicates a platelet-specific ability to induce alloimmunization. Therefore, factors enhancing platelet internalization may be identified as risk factor for alloimmunization by platelet concentrates. To investigate if storage of platelets is such a risk factor, internalization of stored platelets was compared with fresh platelets and showed enhanced internalization of stored platelets. Storage-induced apoptosis and accompanied phosphatidylserine exposure seemed to be instrumental for this. Indeed, DCs pre-incubated with apoptotic platelets induced the strongest IFN-γ production by CD4 T cells compared with pre-incubation with untreated or activated platelets. In conclusion, this study shows the capacity of platelets to induce platelet-specific alloimmune responses. Furthermore, storage-induced apoptosis of platelets is identified as potential risk factor for alloimmunization after platelet transfusions.
KW - Antigen Presentation/immunology
KW - Apoptosis
KW - Blood Platelets/immunology
KW - Dendritic Cells/immunology
KW - Histocompatibility Antigens Class II/immunology
KW - Humans
KW - Immunization
KW - Isoantibodies/immunology
KW - Phagocytosis/immunology
KW - Platelet Transfusion/adverse effects
KW - Risk Factors
KW - T-Cell Antigen Receptor Specificity
KW - T-Lymphocytes/immunology
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85048139565&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29951051
UR - https://pure.uva.nl/ws/files/128268258/Supplementary_Material_Storage_Induced_Platelet_Apoptosis_1.pdf
UR - https://pure.uva.nl/ws/files/128268260/Supplementary_Material_Storage_Induced_Platelet_Apoptosis_2.pdf
UR - https://pure.uva.nl/ws/files/128268262/Supplementary_Material_Storage_Induced_Platelet_Apoptosis_3.pdf
UR - https://pure.uva.nl/ws/files/128268264/Supplementary_Material_Storage_Induced_Platelet_Apoptosis_4.pdf
UR - https://pure.uva.nl/ws/files/128268266/Supplementary_Material_Storage_Induced_Platelet_Apoptosis_5.pdf
U2 - https://doi.org/10.3389/fimmu.2018.01251
DO - https://doi.org/10.3389/fimmu.2018.01251
M3 - Article
C2 - 29951051
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JUN
M1 - 1251
ER -