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Effects of alloantibodies to human leukocyte antigen on endothelial expression and serum levels of thrombomodulin
Author(s) -
Béland S.,
Vallin P.,
Désy O.,
Lévesque E.,
De Serres S. A.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13661
Subject(s) - thrombomodulin , human leukocyte antigen , antibody , immunology , antigen , endothelial stem cell , medicine , biology , platelet , in vitro , thrombin , biochemistry
Essentials The effect of alloantibodies on the endothelial expression of thrombomodulin is unknown. Thrombomodulin was quantified in stimulated endothelial cells and measured in serum samples. Anti‐human leukocyte antigen (HLA) I vs. II antibodies have different effects on thrombomodulin. Anti‐HLA II antibodies may promote a prothrombotic state and contribute to microangiopathy.Summary Rationale Thrombomodulin ( TBM ) is an anticoagulant and anti‐inflammatory transmembrane protein expressed on endothelial cells. Donor‐specific alloantibodies, particularly those against human leukocyte antigen ( HLA ) class II , are associated with microvascular endothelial damage in solid allografts. Objective Our aim was to characterize the effects of anti‐ HLA antibodies on endothelial expression of TBM , and in particular, the differential effects of anti‐ HLA class I compared with those of anti‐ HLA class II . Methods We used human glomerular microvascular endothelial cells to examine TBM expression on anti‐ HLA ‐treated cells, and we tested sera from transplant recipients for soluble TBM . Results We found that whereas membrane TBM expression increased in a dose‐dependent manner in the presence of anti‐ HLA class I antibodies, treatment with anti‐ HLA class II led to minimal TBM expression on the endothelial surface but to a cytosolic accumulation. Platelet adhesion studies confirmed the functional impact of anti‐ HLA class II . Quantitative densitometry of the membrane lysates further suggested that anti‐ HLA class II impairs TBM glycosylation. Furthermore, we found a significant association between the presence of circulating anti‐ HLA class II antibodies in transplant recipients and low serum levels of TBM . Conclusion These results indicate that ligation of anti‐ HLA class I and II antibodies produces different effects on the endothelial expression of TBM and on serum levels of TBM in transplant recipients. Anti‐ HLA class II antibodies may be associated with a prothrombotic state, which could explain the higher occurrence of microangiopathic lesions in the allograft and the poor outcomes observed in patients with these alloantibodies.