The role of lymphocyte apoptosis in septic shock remains a controversial issue. Using Annexin V and flow cytometry analysis on freshly isolated cells, we evaluated circulating lymphocyte apoptosis in 23 septic shock, 25 sepsis without shock, 7 nonseptic critically ill, and 25 control patients. In patients with sepsis, we compared day 1 lymphocyte apoptosis (i.e., within 3 days of the onset of infection) with that observed 5-7 days after (day 6) according to shock state, mortality, and seventy factors. At day 1, patients in septic shock exhibited higher lymphocyte apoptosis than that present in controls (16.5% +/- 3.5% vs. 3% +/- 0.5%, respectively, P = 0.0001). At day 6, patients with sepsis without shock restored undamaged CD4+ T and CD8+ T lymphocyte counts, whereas patients in septic shock increased only CD4+ T cells. Similarly, survivors restored undamaged lymphocyte count at day 6 (+70%, P < 0.001), whereas nonsurvivors did not. Day 6 undamaged lymphocyte count negatively correlated with day 1 SAPS II, day 6 LOD score, mechanical ventilation, and ICU stay duration. We observed no apoptotic effect of septic shock plasma or septic shock circulating mononuclear cells on target lymphoid cell lines. We found no alteration in any death receptors Fas, TRAIL-R1, TRAIL-R2, or in their ligands on circulating blood cells. Catecholamines and interleukin 10 levels significantly increased in patients with septic shock, but did not correlate with apoptosis levels. We conclude that lymphocyte apoptosis is rapidly increased in blood of patients in septic shock and that lymphocyte apoptosis leads to a profound and persistent lymphopenia associated with poor outcome. These results suggest that lymphocyte apoptosis is one of the main components of human septic shock immune dysfunction and could be related more to microcirculatory disturbance than to circulating factors.

Monocyte deactivation has been identified as a major factor of immunosuppression in sepsis and is associated with a loss of surface human leukocyte antigen-DR (HLA-DR) expression on circulating monocytes. Using flow cytometry, quantitative reverse transcription-polymerase chain reaction, we investigated this phenomenon in septic patients. We confirmed the early loss of monocyte HLA-DR expression in all infected patients and demonstrated that this persistent lowered expression at Day 6 correlated with severity scores, secondary infection, and death. This phenomenon occurred at a transcriptional level via a decrease in the class II transactivator A (CIITA) transcription. Furthermore, these abnormalities correlated with the high cortisol levels observed in sepsis and not with those of other putative factors such as catecholamines or interleukin-10. Finally, in vitro studies evidenced that glucocorticoids decrease HLA-DR expression at a transcriptional level via a decrease in CIITA mRNA levels, mainly by down modulating its isoforms I and III. We conclude that in human sepsis, the loss of HLA-DR expression on circulating monocytes is associated with a poor outcome. We suggest that the high endogenous cortisol level observed in septic shock may be a possible new factor involved in the loss of HLA-DR expression on monocytes via its effect on HLA-DR and CIITA transcription.

HLA‐G displays immunotolerogenic properties towards the main effector cells involved in graft rejection through inhibition of NK‐ and CTL‐mediated cytolysis and CD4+ T cell alloproliferation. HLA‐G expression is restricted in healthy tissues to trophoblast and thymus but is extended to various tissues under pathological conditions. HLA‐G was detected in allograft biopsies and sera from transplanted patients who displayed a better graft acceptance. However, the cells involved in such de novo expression of HLA‐G remain to be characterized. By flow cytometry and confocal microscopy, we demonstrated that, following allogeneic stimulation in vitro, both CD4+ and CD8+ T cell subsets can express membrane‐bound HLA‐G1 and/or soluble HLA‐G5molecules. Such HLA‐G1/‐G5 expression is regulated at the transcriptional level. Soluble HLA‐G5 could be detected by using a novel monoclonal antibody, 5A6G7, specific for the intron 4‐retaining sequence of HLA‐G5. Finally, the biological relevance of these data was provided by analysis of transplanted patients in whom we identified both CD4+ and CD8+ T cells expressing HLA‐G. The HLA‐G‐positive T cells we describe here may constitute a cellular source of HLA‐G after allotransplantation and may be involved in the improved graft acceptance which is observed in HLA‐G‐positive transplanted patients.

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.