Talk:Trophoblast - Protein Expression
HLA-G 2012 conference: the 15-year milestone update
Tissue Antigens. 2013 Mar;81(3):127-36. doi: 10.1111/tan.12053. Epub 2013 Jan 24.
Loustau M1, Wiendl H, Ferrone S, Carosella ED. Author information
Abstract The non-classical human leukocyte antigen (HLA) Class I molecule HLA-G is best known for its tolerogenic function at the maternal-fetal interface, where it protects the fetus from destruction by the immune system of its mother. Yet, HLA-G has been the topic of intense investigations and its functions reach much further than originally believed. International conferences on HLA-G have taken place every 3 years since 1998, and the Sixth International Conference on HLA-G, that took place in Paris in July 2012. It counted 180 attendees from 28 countries, 35 speakers in plenary sessions, and 63 presentations of research in symposia and poster sessions, bringing new insight in HLA-G research. Here we summarize the major advances on the function and nature of HLA-G molecule that were reported, with particular interest on the findings in new mechanisms of action through regulatory cells, its relevance in cancer as well as in the molecular structure and functions of HLA-G, which are key for its clinical application. © 2013 John Wiley & Sons A/S.
PMID 23347068
Molecular pathways: human leukocyte antigen G (HLA-G)
Clin Cancer Res. 2013 Oct 15;19(20):5564-71. doi: 10.1158/1078-0432.CCR-12-3697. Epub 2013 Jul 29.
Curigliano G1, Criscitiello C, Gelao L, Goldhirsch A. Author information
Abstract Human leukocyte antigen G (HLA-G) is a nonclassical MHC class I molecule that exerts important tolerogenic functions. Its main physiologic expression occurs in the placenta, where it participates in the maternal tolerance toward the fetus. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. It is expressed in various types of primary solid (melanoma, head and neck, lung, urogenital, gastrointestinal, and breast cancers) and hematologic malignancies (acute leukemia, lymphomas) and metastases. HLA-G ectopic expression is observed in cancer, suggesting that its expression is one strategy used by tumor cells to escape immune surveillance. In this review, we will focus on HLA-G expression in cancers and its association with the prognosis. We will highlight the underlying molecular mechanisms of impaired HLA-G expression, the immune tolerant function of HLA-G in tumors, and the potential diagnostic use of membrane-bound and soluble HLA-G as a biomarker to identify tumors and to monitor disease stage. As HLA-G is a potent immunoinhibitory molecule, its blockade remains an attractive therapeutic strategy against cancer. Elimination of HLA-G-expressing cancer cells would be important in the efficacy of anticancer therapies. ©2013 AACR.
PMID 23897901
Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors
Cell Mol Life Sci. 2012 Jul 17. [Epub ahead of print]
Howangyin KY1, Loustau M, Wu J, Alegre E, Daouya M, Caumartin J, Sousa S, Horuzsko A, Carosella ED, Lemaoult J. Author information
Abstract The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α(1)-α(2)-α(3) non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5. In the present work, we studied the capability of all isoforms to form homomultimers, and investigated whether they could bind to, and function through, the known HLA-G receptors LILRB1 and LILRB2. We report that all HLA-G isoforms may form homodimers, demonstrating for the first time the existence of HLA-G4 dimers. We also report that the HLA-G α(1)-α(3) structure, which constitutes the extracellular part of HLA-G2 and HLA-G6, binds the LILRB2 receptor but not LILRB1. This is the first report of a receptor for a truncated HLA-G isoform. Following up on this finding, we show that the α(1)-α(3)-Fc structure coated on agarose beads is tolerogenic and capable of prolonging the survival of skin allografts in B6-mice and in a LILRB2-transgenic mouse model. This study is the first proof of concept that truncated HLA-G isoforms could be used as therapeutic agents. PMID 22802125
HLA-G in human reproduction: aspects of genetics, function and pregnancy complications
Hum Reprod Update. 2006 May-Jun;12(3):209-32. Epub 2005 Nov 9.
Hviid TV. Author information
Abstract
The non-classical human leukocyte antigen (HLA) class Ib genes, HLA-E, -G and -F, are located on chromosome 6 in the human major histocompatibility complex (MHC). HLA class Ib antigens resemble the HLA class Ia antigens in many ways, but several major differences have been described. This review will, in particular, discuss HLA-G and its role in human reproduction and in the human MHC. HLA-G seems to be important in the modulation of the maternal immune system during pregnancy and thereby the maternal acceptance of the semiallogenic fetus. Recent findings regarding aspects of HLA-G polymorphism, the possible significance of this polymorphism in respect to HLA-G function and certain complications of pregnancy (such as pre-eclampsia and recurrent spontaneous abortions (RSA)) are discussed together with possible importance to IVF. Finally, aspects of a possible role of HLA-G in organ transplantation and in inflammatory or autoimmune disease, and of HLA-G in an evolutionary context, are also briefly examined.
PMID 16280356
The non-classical Human Leukocyte Antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions.
trophoblast cells, which originate from the fetus, do not express classical HLA class Ia and II antigens, except for a possible weak expression of HLA-C
Major histocompatibility complex (MHC)
- short arm of chromosome 6, ∼4 Mb and encodes at least ∼130 functional genes.
- classical HLA class Ia and II genes (HLA-A, -B, -C, -DR, -DQ and -DP)
- non-classical HLA class Ib genes
- HLA class Ib antigens, HLA-E, -F and -G
fetus inherits one HLA haplotype from the mother and one from the father and is thereby semiallogenic for the mother.
HLA-G
- gene is located on chromosome 6 close to HLA-A
- inhibit cytotoxic T-lymphocyte (CTL) response
- inhibit natural killer (NK) functions
- in both cases by direct interaction with the receptors ILT2 and ILT4 and with the killer Ig-like receptor 2 DL4 (KIR2DL4 receptor)
- short cytoplasmic tail important for reduced spontaneous endocytosis of HLA-G
- seven HLA-G mRNA and protein isoforms are generated by alternative splicing of mRNA.
- four membrane-bound isoforms (HLA-G1 to -G4)
- three soluble isoforms (HLA-G5, -G6, -G7)
- HLA-G mRNA has been detected in many different tissues, HLA-G protein expression has been described repeatedly only on and by the trophoblast cells in placenta on and by certain immune cells (in most cases monocytes) and in the thymus
Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the feral-maternal interface
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3360-5. Epub 2005 Feb 17.
Clements CS1, Kjer-Nielsen L, Kostenko L, Hoare HL, Dunstone MA, Moses E, Freed K, Brooks AG, Rossjohn J, McCluskey J. Author information
Abstract HLA-G is a nonclassical major histocompatibility complex class I (MHC-I) molecule that is primarily expressed at the fetal-maternal interface, where it is thought to play a role in protecting the fetus from the maternal immune response. HLA-G binds a limited repertoire of peptides and interacts with the inhibitory leukocyte Ig-like receptors LIR-1 and LIR-2 and possibly with certain natural killer cell receptors. To gain further insights into HLA-G function, we determined the 1.9-A structure of a monomeric HLA-G complexed to a natural endogenous peptide ligand from histone H2A (RIIPRHLQL). An extensive network of contacts between the peptide and the antigen-binding cleft reveal a constrained mode of binding reminiscent of the nonclassical HLA-E molecule, thereby providing a structural basis for the limited peptide repertoire of HLA-G. The alpha3 domain of HLA-G, a candidate binding site for the LIR-1 and -2 inhibitory receptors, is structurally distinct from the alpha3 domains of classical MHC-I molecules, providing a rationale for the observed affinity differences for these ligands. The structural data suggest a head-to-tail mode of dimerization, mediated by an intermolecular disulfide bond, that is consistent with the observation of HLA-G dimers on the cell surface.
PMID 15718280
