Classical and non-classical HLA class I antigens as well as NK-cell activating lig-ands are expressed not only on cell membranes, but also in plasma [4, 41-43]. Classical HLA class I antigens are expressed as soluble molecules or bound to membranous nanoparticles or microvesicles  (Fig. 2.4). Whether HLA-G and NK-cell activating ligands are also bound to microvesicles is not known. Distinct mechanisms underlie their release from cells. They include secretion, proteolytic cleavage and metalloprotease-mediated cleavage of membrane bound molecules and alternative splicing. As a result different isoforms of classical and non-classical HLA class I antigens are present in plasma [41-43]. In view of the frequent loss of P2 m by malignant cells, it is noteworthy that both classical and non-classical HLA class I antigens have been detected in plasma not only as HLA class I heavy chain-P2 m-peptide complexes, but also as P2 m-free heavy chains. The latter maintain most, if not all the functional activities of P2 m-associated HLA class I heavy chains [41-43].
The functional role of soluble classical and non-classical HLA class I antigens as well as NK-cell activating ligands is not known. It is likely that they play a role in immunological phenomena, since they are immunologically active, as indicated by their reactivity with antibodies and/or with T cell receptors as well as by their immunogenicity in autologous, allogeneic and xenogeneic combinations [2, 27]. Furthermore, as already mentioned, the serum levels of classical and non-classical HLA class I antigens and of NK-cell activating ligands change in some pathological conditions; in some diseases these changes are associated with the clinical
Fig. 2.4 HLA class I and class II antigen expression on microvesicles isolated from sera of (pt) patients with head and neck cancer (HNC) or melanoma (mel) or from superna-tants of the SCCHN cell line PCI-13, of the melanoma cell lines mel 1 and mel 2, of the ovarian carcinoma cell line OVCa and of human dendritic cells (DC). Western blot analysis was performed with the HLA class I heavy chain-specific mAb HC-10 and with the HLA class II Bchain-specific mAb LGII-612.14
course of the disease [2, 4, 24, 25, 41]. However, to the best of our knowledge, in no case a cause-effect relationship between these two phenomena has been described.
Convincing evidence indicates that classical HLA class I antigens can induce apoptosis of activated CD8 T cells in vitro utilizing Fas-Fas ligand interactions [44, 63]. A similar result has been obtained for the non-classical HLA class I antigens HLA-G by Fournel et al.  and by us , although this finding has not been confirmed by Hunt  who has used recombinant HLA-G in her experiments. There is conflicting information about the mechanisms underlying the induction of apoptosis of activated T cells. The series of reactions leading to apoptosis of activated T cells is triggered by the interaction of HLA class I antigens with T cell receptors (TCR), according to Zavazava and Kronke , but with CD8 according to our own data [6, 44]. Furthermore there are conflicting data about the potency of classical and non-classical HLA class I antigens in inducing apoptosis of activated T cells. According to Fournel et al.  non-classical HLA class I antigens are more potent than classical HLA class I antigens, while the reverse is true according to our own data . At any rate HLA class I antigens released from tumor cells in their microenvironment provide a mechanism for the presence of apoptotic T cells in the tumor microenvironment .
NK-cell activating ligands are also released from tumor cells by the activity of metalloproteases [21, 50, 57]. This causes not only downregulation of their expression on tumor cell membrane, but also promotes a reversible downregulation of NKG2D on NK and CD8 T cells because of its internalization [21, 50]. These changes have a negative impact on the immunosurveillance mediated by cytotoxic cells. Specifically the reduced expression of NK-cell activating ligands decreases the immunogenicity of tumor cells which is influenced by the density of NK-cell activating ligands on cell membrane. Furthermore the reduced surface NKGD2 expression impairs the cytotoxic activity of tumor antigen-specific CTL and of NK cells . The causal role played by soluble NK-cell activating ligands in these phenomena is indicated by the results recently published by Dranoff and his collaborators . The development of MICA-specific antibodies in patients treated with anti-CTLA-4 monoclonal antibodies or immunized with autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor was associated with a decrease in the levels of soluble MICA in serum and an increase in the expression of NKG2D on NK cells and CD8+ T cells and their cytotoxicity.
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Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.