R. Fauchet

Nomenclature for Factors of the HLA System, 1996

Recently a number of new genes have been identified within the HLA region including some whose functions are related to HLA class I and I1 genes. The Committee discussed what its strategy should be for the naming of these and further new Julia G. Bodmer, Steven 6. E. Marsh, Ekkehard D. Albert, Walter F. Bodmer, Ronald E. lontrop, Dominique Charron, Bo Dupant, Henry A. Erlich, Renee Fauchet, Bernard Mach, Wolfgang R. Mayr, Peter Parham, Takehlko Sasazuki, Geziena M. Th. Schreuder, Jack 1. Strominger, Arne Svejgaard and Paul la Terasaki

HLA-DR-Mediated Apoptosis Susceptibility Discriminates Differentiation Stages of Dendritic/Monocytic APC

Professional APC are characterized by their ability to present peptide via HLA class II in the presence of costimulatory molecules (CD40, CD80, and CD86). The efficiency of Ag presentation can be classed as follows: mature dendritic cells (DC) are most efficient, immature DC and macrophages are intermediate, and monocytes are considered poor APC. There is a large body of evidence demonstrating that HLA-DR transmits signals in the APC. In this study, we have addressed the question of the outcome of HLA-DR signals on APC of the monocyte/DC lineages throughout their differentiation from immature to mature APC. DC were generated from both monocytes and CD34+ cells of the same individual, macrophages were differentiated from monocytes. Immunophenotypical analysis clearly distinguished these populations. HLA-DR-mediated signals led to marked apoptosis in mature DC of either CD34 or monocytic origin. Significantly less apoptosis was observed in immature DC of either origin. Nonetheless, even immature DC were more susceptible to HLA-DR-mediated apoptosis than macrophages, whereas monocytes were resistant to HLA-DR-mediated apoptosis. The mechanism of HLA-DR-mediated apoptosis was independent of caspase activation. Taken together, these data lead to the notion that signals generated via HLA-DR lead to the demise of mature professional APC, thereby providing a means of limiting the immune response.

Modulation of HLA-G antigens expression in myelomonocytic cells

As trophoblast cells and macrophages share cellular characteristics, we investigated the expression of HLA-G antigens during the myelomonocytic differentiation. Analyses with the 87G and 16G1 monoclonal antibodies demonstrated that HLA-G was not expressed in peripheral blood monocytes, in in vitro differentiated dendritic cells and macrophages, and in resident mononuclear phagocytes infiltrating healthy tissues. Conversely, activated macrophages and dendritic cells localized in tumoral biopsies of some lung carcinomas expressed HLA-G antigens. Induction of HLA-G expression at the cell surface of the monohistiocytic cell line U 937 with different cytokines strongly suggests that cytokines secreted during inflammation may be involved in this specific upregulation. Bronchoalveolar macrophages collected from patients suffering from acute HCMV pneumonitis also expressed HLA-G molecules. In vitro, we thus demonstrated that HLA-G antigens are produced during viral reactivation in the macrophages generated after allogeneic stimulation of HCMV latently infected monocytes. Our data suggest that inflammatory processes in lung tissues, like tumoral transformation and HCMV acute infection, are likely to induce HLA-G molecules in infiltrating macrophages and dendritic cells. The expression of molecules capable of downregulating both the innate and adoptive immunity could be a mechanism that helps tumoral and HCMV infected cells to escape immune response.

An in vitro model of allogeneic stimulation of cord blood: induction of Fas independent apoptosis.

Cord blood is increasingly used in transplantation as it is a readily available source of progenitor cells and is reputed to generate less severe graft-versus-host disease (GVHD) than adult bone marrow. We have compared apoptosis of cord blood lymphocytes (CB) and adult lymphocytes (PBMC) after stimulation via HLA class I, HLA class II or CD3 in order to reproduce in vitro some of the stimuli occurring after allotransplantation. CB spontaneously apoptose more than PBMC ex vivo, stimulation via HLA class I dramatically increased CB apoptosis without altering viability of PBMC. Expression of Fas was markedly lower on CB than on PBMC and this difference was maintained even after activation. Fas ligand was expressed in CB and in PBMC. CB were activated via either HLA class I or class II molecules although proliferation was not observed. Only phorbol ester pre-activation allowed Fas to subsequently induce a death signal. Proliferation of PBMC via CD3 led to enhanced Fas signals. CB therefore differ from PBMC with regard to both spontaneous and activation induced apoptosis and either allo- or CD3 mediated stimulation. Finally, the apoptosis of CB via HLA-class I could have an important role in the moderation of graft-versus-host disease.

HLA-DR mediated cell death is associated with, but not induced by TNF-α secretion in APC

Abstract Tumor necrosis factor α (TNFα) is a pleiotropic cytokine involved in inflammatory responses which can trigger both cell apoptosis and cell activation. In antigen presenting cells (APC), TNFα increased antigen presentation, notably by up-regulation of HLA class II expression. In addition to their role in antigen presentation, HLA-DR molecules transduce intracellular signals which lead to cytokine up-regulation or cell death. We have previously observed that the susceptibility of APC to HLA-DR mediated apoptosis increase throughout their maturation. We therefore investigated the relationship between TNFα production and susceptibility to HLA-DR-mediated apoptosis of different APC. The hematopoietic progenitor cell line (KG1), monocytic cell line (THP-1), monocyte-derived dendritic cell (DC), and B-lymphoid cell line (Raji) have been studied. We report that apoptosis susceptibility and spontaneous TNFα release are correlated in these different cells. However, while autocrine TNFα production was critical for DC maturation, upregulation of TNFα release after HLA-DR crosslinking was not observed and neutralization of endogenous TNFα did not modify HLA-DR-mediated apoptosis. These data reveal that HLA-DR mediated apoptosis susceptibility and spontaneous TNFα release are regulated in a parallel manner and that while TNFα may induce maturation of APC to an “apoptosis sensitive” stage, there is no direct role for TNFα in HLA-DR-mediated apoptosis of APC.

HLA Diversity of Alleles and Haplotypes. The Contribution of the 12th International Histocompatibility Workshop

The field of HLA has never been so dynamic at the forefront of science and medicine. A precise knowledge of the genetic diversity of the HLA region requires to analysis new genes, new alleles, new polymorphisms, and new haplotypes along with the distribution of these in various population of the world.