Expression of functional soluble human leucocyte antigen‐G molecules in lymphoproliferative disorders

Abstract

Summary Membrane‐bound and soluble human leucocyte antigen‐G (sHLA‐G) molecules display immunotolerant properties favouring tumour cell escape from immune surveillance. sHLA‐G molecules have been detected in several tumour pathologies; this study aimed to evaluate sHLA‐G expression in lymphoproliferative disorders. sHLA‐G plasma level was significantly increased in 110 of 178 newly diagnosed lymphoid proliferations cases i.e. 59% of chronic lymphocytic leukaemia, 65% of B non‐Hodgkin lymphomas (NHL) and 58% of T‐NHL. To assess the mechanisms involved in this secretion, the differential effect of cytokines was tested in in vitro cultures of NHL cells. A significant induction of sHLA‐G level was shown in T‐NHL in contrast with B‐NHL and normal equivalent cells, after cytokine stimulation with (i) interferonγ (IFNγ), interleukin‐2 (IL‐2) and granulocyte‐macrophage colony‐stimulating factor, (ii) IL‐10 and (iii) transforming growth factor β. An impact of microenvironment on sHLA‐G expression was found in B‐NHL as shown by the in vitro effect of addition of normal monocytes. Finally, a functional effect of sHLA‐G molecules purified from pathologic plasma was demonstrated by their strong capacity to inhibit T‐cell proliferation at concentrations currently observed during these disorders. These results suggest that functional sHLA‐G molecules are upregulated in lymphoproliferative disorders which can support their potential immunomodulatory role during this pathology.

Differential Effects of HNF-1α Mutations Associated with Familial Young-Onset Diabetes on Target Gene Regulation

“…If this activation is stronger than the inhibition due to immunosuppressants, it can lead to a rejection response manifested by the production of Th1-type cytokines, especially IL-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, as well as a change in the Th1/Th2 balance. These cytokines have been shown to downregulate HLA-G expression (34,35).…”

CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis

“…Furthermore, higher levels correlated with increased immunosuppression as judged by immunoglobulin-G levels, CD4 ϩ T cells, and total T-cell numbers. 26,27 HLA-G expression has also been studied in patients with non-Hodgkin lymphoma (NHL). Although one study showed no expression, 28 other studies reported 65%-100% HLA-G expression in B-NHL, 29 and 58% expression in T-NHL.…”

Beyond the increasing complexity of the immunomodulatory HLA-G molecule

“…by guest www.bloodjournal.org From situation might for be that of liver-kidney transplanted patients, in which HLA-G expression is pathologically highly significant. 56,78 However, in cases where monomers are present, results should yield results similarly positive but not pathologically significant for lack of functional relevance of monomers, and this might account for numerous reports of lack of association between sHLA-G and pathologic status (eg, Sebti et al 70 ). It is now clear that the relationship between HLA-G structure and its functional relevance needs to be established beyond doubt in vivo, and that for this, new analytical tools have to be developed to specifically detect and study the most active HLA-G structures.…”

“…Alternatively, HLA-G could be blocked or deleted as a contributor to tumor immunosuppression and/or tumoral escape. 70 Recently, new aspects of HLA-G biology have been reported that are critical to HLA-G pathologic relevance and should help design HLA-G-based diagnosis and therapeutic strategies. First is the description of HLA-G multiple structures and the demonstration that HLA-G multimers carry most, if not all, of HLA-G inhibitory function.…”