112 research outputs found
Analyse critique du modèle immunologique du soi et du non-soi et de ses fondements métaphysiques implicites
www.sciencedirect.comNational audienceAn examination of the concepts used in immunology prompts us to wonder about the origins and the legitimacy of the notions of self and non-self, which constitute the core of the dominant theoretical model in this science. All theoretical reflection concerning immunology must aim at determining a criterion of immunogenicity, that is, an operational definition of the conditions in which an immune reaction occurs or does not occur. By criticizing both conceptually and experimentally the self/non-self vocabulary, we can demonstrate the inaccuracy and even the inadequacy of the dichotomy of self/non-self. Accordingly, the self/non-self model must be reexamined, or even rejected. On the basis of this critique, we can suggest an alternative theoretical hypothesis for immunology, based on the notion of continuity. The 'continuity hypothesis' developed here attempts to give a criterion of immunogenicity that avoids the reproaches leveled at the self model.Un examen des concepts utilisés par l'immunologie conduit à s'interroger sur l'origine et la légitimité des notions de soi et de non-soi, situées au coeur du modèle théorique dominant dans cette science. Toute réflexion théorique sur l'immunologie doit se donner pour fin la détermination d'un critère d'immunogénicité, c'est-à-dire la définition opératoire des conditions dans lesquelles une réaction immunitaire a lieu ou n'a pas lieu. Or, une double critique, conceptuelle d'une part et fondéesur des résultats expérimentaux d'autre part, du vocabulaire du soi et du non-soi, permet de montrer l'imprécision et même l'inadéquation de la dichotomie soi/non-soi. Il apparaît alors que le modèle du soi et du non-soi doit être revu, voire rejeté. À partir de cette critique, on peut proposer une autre hypothèse théorique pour l'immunologie, fondée sur la notion decontinuité. L'« hypothèse de la continuité » présentée ici s'efforce de suggérer un critère d'immunogénicité échappant aux reproches précédemment adressés au modèle du soi
HLA-G/LILRBs: A Cancer Immunotherapy Challenge.
Despite some success, many patients do not benefit from immunotherapy. New strategies to improve clinical efficacy include identification of novel immune-checkpoint (IC) targets or a combination of immunotherapy with antiangiogenic treatments. Here, we propose the therapeutic use of IC, HLA-G/LILRB, and explore its enhanced synergistic antitumor activity when combined with antiangiogenic therapies
Expression of HLA-G in human cornea, an immune-privileged tissue.
Human leukocyte antigen (HLA)-G retains the capacity to modulate immune responses, favoring the establishment of tolerance in solid-tissue allotransplants. To better understand the mechanisms that promote corneal allograft survival, we investigated whether HLA-G was an immunoregulatory factor involved in corneal immunology. We therefore sought HLA-G expression in corneal tissues. Corneal transplantation consists in replacing the center of a diseased cornea with normal corneal tissue. Two corneal parts are not used in such surgery: diseased central corneal tissue and peripheral normal cornea. For this study, we used healthy corneas obtained from deceased donors and diseased corneas obtained from patients with pseudophakic bullous keratopathy or keratoconus who had undergone corneal transplantation. Immunohistochemical analysis carried out on the cryopreserved corneas showed a positive immunohistochemical staining with anti-HLA-G, anti-HLA-A, -B, and -C, and anti-HLA class I monoclonal antibodies. Staining was obtained for keratocytes, epithelial cells, and endothelial cells from both healthy and pathologic human corneas, revealing the presence of HLA class I proteins, including HLA-G. HLA-G transcripts were detected in normal cornea by reverse transcriptase-polymerase chain reaction with a classical pattern of alternative splicing. The detection of HLA-G protein in adult corneas leads to the conclusion that this protein may contribute to the maintenance of the privileged immune status of cornea
HLA-G*0105N null allele encodes functional HLA-G isoforms.
Expression of the nonclassical HLA class I antigen, HLA-G, is associated with immune tolerance in view of its role in maintaining the fetus in utero, allowing tumor escape, and favoring graft acceptance. Expressed on invasive trophoblast cells, HLA-G molecules bind inhibitory receptors on maternal T lymphocytes and NK cells, thereby blocking their cytolytic activities and protecting the fetus from maternal immune system attack. The HLA-G gene consists of 15 alleles, including a null allele, HLA-G*0105N. HLA-G*0105N presents a single base deletion, preventing translation of both membrane-bound (HLA-G1) and full-length soluble isoforms (HLA-G5) as well as of the spliced HLA-G4 isoform. The identification of healthy subjects homozygous for this HLA-G null allele suggests that the HLA-G*0105N allele may generate other HLA-G isoforms, such as membrane-bound HLA-G2 and -G3 and the soluble HLA-G6 and -G7 proteins, which may substitute for HLA-G1 and -G5, thus assuming the immune tolerogeneic function of HLA-G. To investigate this point, we cloned genomic HLA-G*0105N DNA and transfected it into an HLA-class I-positive human cell line. The results obtained indicated that HLA-G proteins were indeed present in HLA-G*0105N-transfected cells and were able to protect against NK cell lysis. These findings emphasize the role of the other HLA-G isoforms as immune tolerogeneic molecules that may also contribute to maternal tolerance of the semiallogenic fetus as well as tumor escape and other types of allogeneic tissue acceptance
Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu
Human leucocyte antigen G (HLA-G) is a tolerogenic molecule that protects the
fetus from maternal immune attack, may favour tumoral immunoescape and is
up-regulated in viral and inflammatory diseases. The aim of this work was to
discover if nitric oxide (NO) could affect HLA-G expression or function because
NO is an important modulator of innate and adaptive immunity. For this purpose
HLA-G expression and function were analysed following treatment with a NO donor
or a peroxynitrite donor in various cell lines expressing HLA-G either
spontaneously or upon transfection. Results showed NO-dependent nitration of both
cellular and soluble HLA-G protein, but not all HLA-G moieties underwent
nitration. Endogenous biosynthesis of NO by both U-937-HLA-G1 and M8-HLA-G5
stable transfectants also caused HLA-G nitration. The NO decreased total HLA-G
cellular protein content and expression on the cell surface, while increasing
HLA-G shedding into the culture medium. This effect was post-transcriptional and
the result of metalloprotease activity. By contrast, NO pretreatment did not
affect HLA-G capability to suppress NK cytotoxicity and lymphocyte proliferation.
Our studies show that NO regulates the availability of HLA-G molecules without
modifying their biological activities
Linking Two Immuno-Suppressive Molecules: Indoleamine 2,3 Dioxygenase Can Modify HLA-G Cell-Surface Expression1
Nonclassical human leukocyte antigen (HLA) class I molecule
HLA-G and indoleamine 2,3 dioxygenase (INDO) in humans and
mice, respectively, have been shown to play crucial immunosuppressive
roles in fetal-maternal tolerance. HLA-G inhibits
natural killer and T cell function by high-affinity interaction with
inhibitory receptors, and INDO acts by depleting the surrounding
microenvironment of the essential amino acid tryptophan,
thus inhibiting T cell proliferation. We investigated whether
HLA-G expression and INDO function were linked. Working
with antigen-presenting cell (APC) lines and monocytes, we
found that functional inhibition of INDO by 1-methyl-tryptophan
induced cell surface expression of HLA-G1 by HLA-G1-
negative APCs that were originally cell-surface negative, and
that in reverse, the functional boost of INDO by high concentrations
of tryptophan induced a complete loss of HLA-G1 cell
surface expression by APCs that were originally cell-surface
HLA-G1-positive. This mechanism was shown to be posttranslational
because HLA-G protein cell contents remained unaffected
by the treatments used. Furthermore, HLA-G cell surface
expression regulation by INDO seems to relate to INDO function,
but not to tryptophan catabolism itself. Potentia
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