Expression of HLA-G in inflammatory bowel disease provides a potential way to distinguish between ulcerative colitis and Crohn's disease.

In addition to being involved in nutrient uptake, the epithelial mucosa constitute the first line of defense against microbial pathogens. A direct consequence of this physiological function is a very complex network of immunological interactions that lead to a strong control of the mucosal immune balance. The dysfunction of immunological tolerance is likely to be a cause of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD). HLA-G is a non-classical major histocompatibility complex (HLA) class I molecule, which is highly expressed by human cytotrophoblast cells. These cells play a role in immune tolerance by protecting trophoblasts from being killed by uterine NK cells. Because of the deregulation of immune system activity in IBD, as well as the immunoregulatory role of HLA-G, we have analyzed the expression of HLA-G in intestinal biopsies of patients with UC and CD. Our study shows that the differential expression of HLA-G provides a potential way to distinguish between UC and CD. Although the reason for this differential expression is unclear, it might involve a different mechanism of immune regulation. In addition, we demonstrate that in the lamina propria of the colon of patients with UC, IL-10 is strongly expressed. In conclusion, the presence of HLA-G on the surface of intestinal epithelial cell in patients with UC lends support to the notion that this molecule may serve as a regulator of mucosal immune responses to antigens of undefined origin. Thus, this different pattern of HLA-G expression may help to differentiate between the immunopathogenesis of CD and UC.

[HLA-G in organ transplantation]. / HLA-G en transplantation d'organes.

The HLA-G molecule plays a crucial role in the protection of the fetus against aggression by the mother's immune system. Recently, it was shown that HLA-G was involved in the protection of the transplanted tissues, via the inhibition of all immune effectors that mediate graft rejection. The inhibitory functions of HLA-G were studied in vitro using allo- and xeno-geneic models, ex vivo on transplanted tissues biopsies, and in an in vivo animal model. In this review, we will summarize recent results which show that HLA-G acts as a regulator of immune function, seems to be directly involved in transplant acceptation, and should be taken into consideration when monitoring transplanted patients' status.

Biology and functions of human leukocyte antigen-G in health and sickness.

In 1998, the first International Conference on human leukocyte antigen-G (HLA-G) was held in Paris. At that time, HLA-G was still a new HLA class I molecule, few aspects of its immunological functions were known, and its expression by tumors was just being described. In 1998, tools to properly study HLA-G were lacking, especially monoclonal antibodies, and three conclusions were drawn after the congress: (i) animal models were needed, (ii) the biology of HLA-G isoforms had to be confirmed, and (iii) HLA-G expression by tumors required clarification. Five years later, these three issues have been addressed. HLA-G is now gaining pace and is investigated for its immuno-inhibitory functions in the context of multiple pathologies. Eighty five oral presentations were given this year for more than 200 investigators working on HLA-G by speakers from over 20 countries. The success of the 3rd International Conference on HLA-G reflects the interest and tremendous work of the many research teams which, over the years, contributed to the publication of more than 500 peer-review articles. We summarize the key points that were presented and discussed during this meeting.

HLA-G protein processing and transport to the cell surface.

Data are presented on the intracellular trafficking of HLA-G protein, taking the unique features of this non-classical molecule into consideration: the existence of seven isoforms resulting from alternative splicing (HLA-G1 to G7), and reduced tail length compared with HLA class I antigens. Biochemical studies and analysis of viral strategies for escaping the host immune system led to the demonstration that (i) both the membrane-bound (HLA-G1) and the soluble (HLA-G5) forms of the molecule require peptide association for cell surface expression, using TAP-dependent or TAP-independent pathways; (ii) peptide loading onto the HLA-G protein plays a critical role in controlling the quality of the molecule reaching the cell surface; (iii) surface expression of truncated HLA-G molecules is possible, and (iv) HLA-G expression may be restricted to soluble HLA-G5. These data reveal that HLA-G presents specific cell trafficking pathways and strongly support the contention that the primary function of HLA-G is as of an inhibitor ligand for immune-competent cells.

[HLA-G: immune tolerance in normal and pathological physiology]. / HLA-G: immunotolérance en physiologie normale et pathologique.

HLA-G is a low polymorphic non-classical major histocompatibility complex class I molecule which can be expressed upon seven isoforms, and whose expression is correlated to immune tolerance situations. Indeed, the expression of HLA-G may allow partially or non histocompatible cells to escape host's immune aimed to eliminate these "foreign" cells. Functions share by HLA-G molecules are the ability to inhibit lysis mediated by natural killer (NK) and by cytotoxic T cells, and to induce apoptosis of activated CD8+ T cells via the HLA-G soluble form. Such model which evades defenses of the immune system was described in the foeto-maternal symbiosis, in tumoral cells or histo-incompatible graft previously. The importance of the role of HLA-G molecules expressed by particular cells as a shield against immune defenses is actually largely studied. The control of HLA-G expression could be used as immunotherapeutic approach, either by up-modulating HLA-G expression in order to favour tolerance of incompatible cells such as foetal cell or graft, or by down-modulating HLA-G expression in order to support the destruction of tumoral cells by cytotoxic T cells. This article reports the recent data on polymorphism, HLA-G gene transcription and implication of HLA-G molecules in immune responses during pregnancy, transplantation or tumoral growth.

Spatial and temporal mapping of c-kit and its ligand, stem cell factor expression during human embryonic haemopoiesis.

Receptor tyrosine kinases (RTKs) mediate cellular responses to the extracellular signals involved in the regulation of cell differentiation and proliferation. Ligand binding initiates a cascade of events, such as receptor dimerization and tyrosine phosphorylation. The c-kit gene encodes an RTK for stem cell factor (SCF), (c-kit ligand, KL), both of which play a critical role in the differentiation and growth of haemopoietic stem cells (HSCs). We investigated the expression of the c-kit and SCF genes and the presence of the corresponding proteins in haemopoietic tissues during human embryogenesis. We have examined c-kit and SCF transcripts levels in human embryonic yolk sac, the AGM region, and liver at different stages of gestation (days 25 to 63), using RT-PCR amplification combined with PhosphorImager quantitative analysis and RNase Protection Assay (RPA). Weak levels of SCF gene expression were observed in the AGM region (days 25 to 34) and high levels were found in the early-stage liver (day 34). The expression of c-kit transcript was observed in all studied tissues, but at various levels. The restricted presence of SCF protein following mRNA expression was demonstrated in embryonic liver CD38+ haemopoietic cells by immunocytochemistry. These observations suggest that the biological function of the c-kit receptor plays an important role in the early stages of human haemopoiesis, and that c-kit/SCF signalling is particularly involved in early human definitive haemopoiesis.