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The subversion mechanisms employed by Helicobacter pylori ( H. pylori) to escape from immune surveillance and to establish persistent infection are poorly understood. Growing evidence indicates that expression of HLA-G, a non-classical major histocompatibility complex molecule, negatively regulates immune responses in pathological conditions, including infectious diseases. In this context, we aimed to evaluate HLA-G expression in the gastric microenvironment of individuals harbouring H. pylori and to correlate it with histological variables. Fifty-four gastric specimens from patients harbouring H. pylori infection were evaluated by immunohistochemistry using anti- HLA-G monoclonal antibody. As a result, HLA-G expression was detected in 43 of 54 specimens harbouring H. pylori. The presence of HLA-G was significantly associated with milder colonization by H. pylori ( P < 0.02), milder inflammatory activity ( P < 0.02) and bacterium histological location in the gastric antrum. This study is the first to explore HLA-G expression in the context of bacterial infection. Whether the biological role of HLA-G during H. pylori infection is beneficial or hazardous for patients remains to be defined. [ABSTRACT FROM AUTHOR]

HLA-G is a molecule that was first known to confer protection to the fetus from destruction by the immune system of its mother, thus critically contributing to fetal-maternal tolerance. The first functional finding constituted the basis for HLA-G research and can be summarized as such: HLA-G, membrane-bound or soluble, strongly binds its inhibitory receptors on immune cells (NK, T, B, monocytes/dendritic cells), inhibits the functions of these effectors, and so induces immune inhibition. HLA-G function may therefore be beneficial because when expressed by a fetus or a transplant it protects them from rejection, or deleterious because when expressed by a tumor, it also protects it from antitumor immunity. This is the primary HLA-G function: that of a checkpoint molecule. Great work has been done in the past years to characterize HLA-G itself, its regulation, its functions and mechanisms of action, and its pathological relevance. We will review this here, focusing on transplantation and oncology because these pathological contexts have been studied the most and also because they best represent the two opposite sides of HLA-G: beneficial to be promoted, or deleterious to be blocked. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5′ upstream regulatory region (5′URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5′URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5′URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection. [ABSTRACT FROM AUTHOR]

The HLA-G (human leukocyte antigen-G) molecule plays a pivotal role in immune tolerance by inhibiting different cell subsets involved in both innate and adaptive immunity. Besides its primary function in maintaining the maternal-fetal tolerance, HLA-G has been involved in a wide range of pathological conditions where it can be either favorable or detrimental to the patient, depending on the nature of the pathology. Although several studies have demonstrated the utmost importance of the 3′ untranslated region (3′UTR) in the HLA-G expression profile, limited data exist on the sequence variability of this gene region in human populations. In this study, we characterized the genetic diversity and haplotype structure of the HLA-G 3′UTR by resequencing 444 individuals from three sub-Saharan African populations and retrieving data from the 1000 Genomes project and the literature. A total of 1936 individuals representing 21 worldwide populations were combined and jointly analyzed. Our data revealed a high level of nucleotide diversity, an excess of intermediate frequency variants and an extremely low population differentiation, strongly supporting a history of balancing selection at this locus. The 14-bp insertion/deletion polymorphism was further pointed out as the likely target of selection, emphasizing its potential role in the post-transcriptional regulation of HLA-G expression. [ABSTRACT FROM AUTHOR]

The human leukocyte antigen-E ( HLA-E) locus is a human major histocompatibility complex ( MHC) gene associated with immune-modulation and suppression of the immune response by the interaction with specific natural killer ( NK) and T cell receptors (TCRs). It is considered one of the most conserved genes of the human MHC; however, this low nucleotide variability seems to be a consequence of the scarce number of studies focusing on this subject. In this manuscript we assessed the nucleotide variability at the HLA-E coding and 3′ untranslated regions (3′UTRs) in Brazil and in the populations from the 1000Genomes Consortium. Twenty-eight variable sites arranged into 33 haplotypes were detected and most of these haplotypes (98.2%) are encoding one of the two HLA-E molecules found worldwide, E*01:01 and E*01:03. Moreover, three worldwide spread haplotypes, associated with the coding alleles E*01:01:01, E*01:03:01 and E*01:03:02, account for 85% of all HLA-E haplotypes, suggesting that they arose early before human speciation. In addition, the low nucleotide diversity found for the HLA-E coding and 3′ UTR in worldwide populations suggests that the HLA-E gene is in fact a conserved gene, which might be a consequence of its key role in the modulation of the immune system. [ABSTRACT FROM AUTHOR]

Host and Plasmodium interactions result in highly variable clinical phenotypes, partly explained by the nature and level of anti-malarial antibody response. Human leukocyte antigen ( HLA)-G can create a tolerogenic environment, allowing parasites to escape from anti-malarial immunity. We performed a family-based association study encompassing 483 Sereer individuals (261 children and their parents), and reported two independent signals at the HLA-G 3′ untranslated region associated with antibody response to specific Plasmodium falciparum blood stage antigens, previously associated with malaria protection: (i) + 3010G together with + 3142C with total IgG and IgG1 against GLURP and (ii) + 3196G with IgG3 against MSP2. While these results require further investigation, they suggest for the first time a role of HLA-G in the regulation of humoral immune response in malaria. [ABSTRACT FROM AUTHOR]

The non-classical human leukocyte antigen (HLA) class I genes present a very low rate of variation. So far, only 10 HLA-E alleles encoding three proteins have been described, but only two are frequently found in worldwide populations. Because of its historical background, Brazilians are very suitable for population genetic studies. Therefore, 104 bone marrow donors from Brazil were evaluated for HLA-E exons 1-4. Seven variation sites were found, including two known single nucleotide polymorphisms (SNPs) at positions +424 and +756 and five new SNPs at positions +170 (intron 1), +1294 (intron 3), +1625, +1645 and +1857 (exon 4). Haplotyping analysis did show eight haplotypes, three of them known as E*01:01:01, E*01:03:01 and E*01:03:02:01 and five HLA-E new alleles that carry the new variation sites. The HLA-E*01:01:01 allele was the predominant haplotype (62.50%), followed by E*01:03:02:01 (24.52%). Selective neutrality tests have disclosed an interesting pattern of selective pressures in which balancing selection is probably shaping allele frequency distributions at an SNP at exon 3 (codon 107), sequence diversity at exon 4 and the non-coding regions is facing significant purifying pressure. Even in an admixed population such as the Brazilian one, the HLA-E locus is very conserved, presenting few polymorphic SNPs in the coding region. [ABSTRACT FROM AUTHOR]

As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)-G is well described as a tolerogenic molecule, we evaluated HLA-G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA-G expression was assessed by immunohistochemistry. No HLA-G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane-bound HLA-G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA-G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached ( P = 0.180), patients exhibiting HLA-G expression presented a higher median HBV DNA viral load (10 copies/mL) than those who did not express HLA-G (10 copies/mL). These results indicate that HLA-G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection. [ABSTRACT FROM AUTHOR]

The human leukocyte antigen (HLA)-G non-classical major histocompatibility complex (MHC) class I molecule was originally described in first-trimester trophoblasts at the fetal–maternal interface in 1990. Eight years later, the First International Conference on this molecule was inaugurated by Prof Jean Dausset, recipient of the Nobel Prize in Medicine. The Fifth International Conference on HLA-G, held in Paris on July 2009, began with a tribute to Prof Jean Dausset who left us recently. This conference was co-chaired by Dr Edgardo D. Carosella and Prof Hans Grosse-Wilde, included 57 oral presentations and was attended by approximately 140 delegates from 16 countries. We summarize here the major advances on the HLA-G molecule that were reported, including findings on its biological activity and characterization of new mechanisms of action, notably through mesenchymal stem cells and regulatory cells, and the previously unexplored role of HLA-G on immune cells such as γδ T-cells and B lymphocytes. Furthermore, the role of HLA-G during pregnancy was revisited and its impact in pathologies such as cancer, autoimmune disorders and transplantation was further extended. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule from the major histocompatibility complex, which was initially shown to confer protection to the fetus from her mother’s immune system. The Third International Conference on HLA-G, held in 2003, showed that beyond its role in fetal–maternal tolerance, HLA-G exerts tolerogenic functions involved in transplant acceptance as well as in tumoral and viral immune escape. The Fourth International Conference, which took place in Paris on July 2006, counted 72 oral presentations and about 200 attendees from 25 countries. The reports presented brought new insight into HLA-G research, and we summarize here the major advances on the HLA-G biology that were reported. Abstracts for all presentations can be found in volume 68 issue number 4 of Tissue Antigens. [ABSTRACT FROM AUTHOR]

A large array of antigens that are recognized by tumor-specific T cells has been identified and shown to be generated through various processes. We describe a new mechanism underlying T cell recognition of melanoma cells, which involves the generation of a major histocompatibility complex class I--restricted epitope after tumor-mediated uptake and processing of an extracellular protein--a process referred to as cross-presentation--which is believed to be restricted to immune cells. We show that melanoma cells cross-present, in an αvβ3-dependent manner, an antigen derived from secreted matrix metalloproteinase-2 (MMP-2) to human leukocyte antigen A*0201-restricted T cells. Because MMP-2 activity is critical for melanoma progression, the MMP-2 peptide should be cross-presented by most progressing melanomas and represents a unique antigen for vaccine therapy of these tumors. [ABSTRACT FROM AUTHOR]

Over the past few years, HLA-G, the non-classical HLA class I molecule, has been the center of investigations that have led to the description of its specific structural and functional properties. Although located in the HLA class I region of chromosome six, the HLA-G gene may be distinguished from other HLA class I genes by its low polymorphism and alternative splicing that generates seven HLA-G proteins, whose tissue-distribution is restricted to normal fetal and adult tissues that display a tolerogeneic function toward both innate and acquired immune cells. We review these points, with special emphasis on the role of HLA-G in human pathologies, such as cancer, viral infection, and inflammatory diseases, as well as in organ transplantation. [ABSTRACT FROM AUTHOR]

Pre-eclampsia is a disorder of human pregnancy occuring in 5-10 % of all births, and represents the leading cause of infant morbidity and mortality and maternal death. In pre-eclampsia, invasion of fetal trophoblasts into maternal arteries during early pregnancy is shallow or absent. Here we examined the hypothesis that HLA-G, a non-classical class I HLA expressed in cytotrophoblasts, may act as a key gene in pre-eclampsia. We analysed HLA-G at the level of transcription and genotyped a silent CAC-CAT polymorphism in exon 3 and a 14-bp insertion/deletion in the 3′ untranslated region. A deficit in levels of the HLA-G3 transcript was observed in mild pre-eclampsia compared to normal placentas. The distribution of HLA-G polymorphisms was different between normal and pre-eclampsia samples. A correlation between the alteration in transcription of the HLA-G gene and certain HLA-G genotypes was also observed. Thus we provide the first evidence for a possible role of HLA-G in genetic susceptibility to, and pathogenesis of pre-eclampsia. [ABSTRACT FROM AUTHOR]

We identified five novel human leukocyte antigen-G alleles with protein-modifying mutations in Caucasian and/or African populations. [ABSTRACT FROM AUTHOR]

Here we report two new non-classical class I HLA-G alleles found in the Brazilian population. [ABSTRACT FROM AUTHOR]

Introduction: Une immunisation humorale dirigée contre les antigènes HLA du greffon a été observée en greffe d’îlots pancréatiques. Nous rapportons chez une patiente diabétique de type 1 non urémique une perte de fonction des îlots greffés en relation avec une immunisation anti HLA suivie d’une récupération fonctionnelle après traitement par anticorps anti-CD20. Observation: Une femme de 51 ans diabétique de type 1 présentant des hypoglycémies sévères avait bénéficié le 18/08/2004 d’une allogreffe îlots pancréatiques (10,295 IEQ/kg) par voie portale à partir d’un seul donneur selon le protocole d’Edmonton. Un mois après la greffe la patiente était devenue insulino indépendante. Les anticorps anti HLA (Ac anti HLA) classe I et II mesurés en pré et post greffe selon la technique ELISA étaient négatifs. Deux ans après la greffe, la réaction Ac anti HLA classe II devenait légèrement positive sans modification du contrôle glycémique. En février 2008, un déséquilibre glycémique apparaissait avec une glycémie à jeun à 8,25 mmol/L, une HbA1 à 6,8 % nécessitant la reprise du traitement insulinique à 10 U/J. Les anticorps anti GAD 65 et IA2 étaient toujours négatifs alors que la réaction Ac anti HLA devenait fortement positive toujours dirigée contre les antigènes de classe II. La technique Luminex disponible uniquement à partir de janvier 2008 et appliquée rétrospectivement à l’ensemble des sérums révélait l’existence d’Ac anti HLA de classe II non spécifiques du donneur dirigés contre l’antigène DR 17 déjà présent avant la greffe. Deux injections IV d’anticorps anti-CD20 associé à une perfusion d’immunoglobulines ont été réalisées à 2 semaines d’intervalle. Un mois après le traitement, les anticorps anti HLA étaient à nouveau négatifs et la patiente insulino-indépendante. Cet effet se maintient à 6 mois. Conclusion: Au cours de la greffe d’îlots, une diminution de fonction des îlots associée à une augmentation des anticorps anti HLA de classe II suggère un rejet humoral des îlots. Le traitement par anticorps anti CD20 doit être discuté. [Copyright &y& Elsevier]

Introduction: La fibrose rétropéritonéale est caractérisée par le développement d’une masse fibreuse autour de structures rétropéritonéales. La fibrose péritonéale est idiopathique dans deux tiers des cas. La physiopathologie n’est pas clairement identifiée. Nous rapportons une observation clinique d’une association de la fibrose péritonéale idiopathique et diabète de type 1. Observation: Il s’agit d’une patiente âgée de 61 ans, présentant un diabète de type 1 depuis l’âge de 43 ans. À 56 ans, est diagnostiquée une hydronéphrose bilatérale par compression urétérale extrinsèque. Le diagnostic de fibrose péritonéale idiopathique est posé. Le diabète est instable sous schéma multi-injections. L’examen clinique (IMC 25) ne retrouve pas l’anomalie particulière sauf une diminution des réflexes ostéotendineux aux membres inférieurs. L’HbA1C est à 8,5 %. Le C peptide est indosable. Les anticorps anti GAD positifs à 5,5 ku/ l (N < 1) et anticorps anti IA2 négatifs. Les haplotypes HLA de classe 2 montrent allèle DRB1*03. L’IgG et l’IgG4 sont normaux. Il n’y a pas de stéatorrhée. Les Ac anti DNA natif et Ac anti nucléaire sont négatifs. Le scanner abdominal ne montre pas de remaniements au niveau du pancréas, mais une dilatation des cavités urétéro-pyélocalicielles en rapport avec la fibrose rétropéritonéale. L’anatomopathologie des biopsies para-urétérales montre un tissu conjontivovasculaire remanié par une fibrose dense dissociée par un infiltrat inflammatoire chronique lympho-plasmocytaire modérément abondant et on conclut à une fibrose inflammatoire chronique. Conclusion: À notre connaissance, il n’y pas précédemment décrit dans la littérature de cas d’association de diabète de type 1 et la fibrose rétropéritonéale. Devant ce diabète très instable avec de nombreuses hypoglycémies avec des besoins modérés en insuline, se pose la question d’une maladie autoimmune associant la fibrose rétropéritonéales et le diabète de type 1 du fait de l’absence de pancréatite chronique autoimmune. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]