Abstract
We and others have found donor-derived soluble β
2m-associated HLA class I proteins (sHLA/β
2m) in the serum of allograft recipients with acute and chronic rejection. Whether appearance of sHLA/β
2m and upregulated expression of donor cell-bound HLA/β
2m during allograft rejection are related events is unknown. Activation-induced upregulation of
in vitro HLA/β
2m expression correlates with the surface expression of another form of HLA class I, namely β
2m-free HLA heavy chains (β
2m-free HC). We have shown that β
2m-free HC, but not β
2m-associated HC, are then cleaved by a specific membrane-bound metalloproteinase and released into supernatants as soluble 36 kDa proteins. We show now that activated peripheral blood lymphocytes produce predominantly the 36 kDa form of sHLA proteins which is present in supernatants as both β
2m-free HC and sHLA/β
2m. Importantly, the metalloprotease inhibitor BB-94 blocked not only the release of soluble β
2m-free HC, but also the appearance of sHLA/β
2m in cell supernatants. Low levels of 36 kDa β
2m-free HC were also present in human plasma of healthy donors. These data suggest an important role for the HLA class I-specific metalloproteinase
in vivo in healthy individuals and during allograft rejection in the generation of soluble β
2m-free and β
2m-associated HLA proteins.