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.