Soluble HLA-G: Are they clinically relevant?

Abstract

HLA-G is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main function in physiological conditions is to abrogate maternal NK cell activity against foetal tissue and to establish immune tolerance at maternal-foetal interface. HLA-G is expressed not only as a membrane bound molecule on the surface of cells, but also as a soluble moiety in body fluids. The major isoforms of HLA-G present in serum are soluble HLA-G1 and HLA-G5 which are generated by shedding or proteolytic cleavage of the membrane bound isoform and by secretion of a soluble isoform, respectively. Here we review the data about soluble HLA-G (sHLA-G) serum levels in different pathological conditions, including immune-mediated disorders, transplantation and malignancies. In particular, we focus on sHLA-G expression and function in human neuroblastoma, a pediatric tumor, with special emphasis on a novel potential immuno escape mechanism utilized by NB to instruct monocytes to produce and release sHLA-G. Finally, the potential clinical relevance of sHLA-G serum levels is discussed.

Figure 1

Immunoregulatory activities mediated by sHLA-G. Target cells and receptors involved are also indicated.

Figure 2

Serum levels of sHLA-G, sHLA-class I, sHLA-class II and sICAM-1 in NB patients. Black and broken lines indicate the mean of serum levels obtained for each molecule in healthy subjects and in NB patients, respectively. Results are expressed as ng/ml for sHLA-G and as arbritrary Units (aU) for the remaining molecules. Only sHLA-G and sICAM-1 are significantly increased in NB patients' sera.

Figure 3

Potential role of epigenetic mechanisms in the differential HLA-G expression by freshly isolated NB cells and by NB cells in long term culture. Panel A. GD2+ cells were purified from BM of two NB patients (right and left panel,), stained with HLA-G1-specific mAb (filled profile) or with an irrelevant isotype-matched mAb (empty profiles) and analyzed with a flow cytometer. Panel B. Cultured NB GI-LI-N cells were cultured for 72 h at 37° C in medium supplemented with 5 μM 5-Aza (right panel) or in medium alone (left panel). Cells were then stained with HLA-G-specific mAb (filled profiles) or with an irrelevant isotype matched mAb (empty profiles) and analyzed with a flow cytometer. Panel C. Cultured NB GI-LI-N cells were cultured for 72 h at 37° C in medium supplemented with trichostatin A (100 ng/ml) (right panel) or in medium alone (left panel). Cells were then stained with HLA-G-specific mAb (filled profiles) or with an irrelevant isotype matched mAb (empty profiles) and analyzed with a flow cytometer.

Figure 4

Schematic representation of a novel mechanism utilized by human neuroblastoma cells to elude the control of the host's immune system. Neuroblastoma cells release soluble factors that activate monocytes to upregulate synthesis and release of soluble HLA-G. This, in turn, inhibits CTL and NK cell mediated cytotoxicity against tumour cells [16].