Non-classical Major Histocompatibility Complex Molecule Research Articles

How the Soluble Human Leukocyte Antigen-G levels in Amniotic Fluid and Maternal Serum Correlate with the Feto-Placental Growth in Uncomplicated Pregnancies.

Introduction: Trophoblast-derived angiogenic factors are considered to play an important role in the pathophysiology of various complications of pregnancy. Human Leukocyte Antigen-G (HLA-G) belongs to the non-classical human major histocompatibility complex (MHC-I) molecule and has membrane-bound and soluble forms. HLA-G is primarily expressed by extravillous cytotrophoblasts located in the placenta between the maternal and fetal compartments and plays a pivotal role in providing immune tolerance. The aim of this study was to establish a relationship between concentrations of soluble HLA-G (sHLA-G) in maternal serum and amniotic fluid at 16-22 weeks of gestation and the sonographic measurements of fetal and placental growth. Materials and methods: sHLA-G in serum and amniotic fluid, as well as fetal biometric data and placental volume and perfusion indices, were determined in 41 singleton pregnancies with no complications. The level of sHLA-G (U/mL) was tested with a sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results: The sHLA-G levels were unchanged both in amniotic fluid and serum during mid-pregnancy. The sHLA-G level in serum correlated positively with amniotic sHLA-G level (β = 0.63, p < 0.01). Serum sHLA-G level was significantly correlated with abdominal measurements (β = 0.41, p < 0.05) and estimated fetal weight (β = 0.41, p < 0.05). Conversely, amniotic sHLA-G level and placental perfusion (VI: β = -0.34, p < 0.01 and VFI: β = -0.44, p < 0.01, respectively) were negatively correlated. A low amniotic sHLA-G level was significantly associated with nuchal translucency (r = -0.102, p < 0.05). Conclusions: sHLA-G assayed in amniotic fluid might be a potential indicator of placental function, whereas the sHLA-G level in serum can be a prognostic factor for feto-placental insufficiency.

The Molecular Mechanisms of HLA-G Regulatory Function on Immune Cells during Early Pregnancy.

Human leukocyte antigen-G (HLA-G) is a non-classical human major histocompatibility complex (MHC-I) molecule with the membrane-bound and soluble types. HLA-G is primarily expressed by extravillous cytotrophoblast cells located at the maternal-fetal interface during pregnancy and is essential in establishing immune tolerance. This review provides a comprehensive understanding of the multiple molecular mechanisms by which HLA-G regulates the immune function of NK cells. It highlights that HLA-G binds to microRNA to suppress NK cell cytotoxicity and stimulate the secretion of growth factors to support fetal growth. The interactions between HLA-G and NK cells also activate senescence signaling, promoting spiral artery remodeling and maintaining the balance of maternal-fetal immune responses. In addition, HLA-G can inhibit the function of decidual T cells, dendritic cells, and macrophages. Overall, the interaction between trophoblast cells and immune cells mediated by HLA-G plays a crucial role in understanding immune regulation at the maternal-fetal interface and offers insights into potential treatments for pregnancy-related diseases.

Identification of Non-classical Follicular T Cells.

Nonclassical T cells are a heterogeneous group of T lymphocytes that are activated during the early stages of infection and act as a bridge between the innate and adaptive immune system. Among them, Natural Killer T (NKT) cells have been extensively studied in the last two decades due to their unique ability to recognize foreign/self-lipid antigens in the context of CD1d, a nonclassical major histocompatibility complex molecule. In this chapter, we describe our protocols to track murine NKT cells in lymph nodes by flow cytometry and confocal microscopy.

Expression of Tolerogenic HLA-G Confer Worse Outcome in Patients with Chronic Lymphocytic Leukemia

Background: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in adults presenting with varied clinical course. There is a higher request for founding known prognostic factors for stratifying CLL patients. HLA-G is a non-classical major histocompatibility complex (MHC) molecule. It can be expressed in membrane bound (m.HLA-G) and soluble forms (s.HLA-G). Objective: The aim of work was to investigate the expression of membrane form of HLA-G in CLL and correlate findings and a variety of clinical and laboratory variables. Patients and methods: This prospective study included a total of thirty newly diagnosed B-CLL patients, attending at Hematology Unit, Medical Oncology Department, national Cancer institute, Cairo. This study was conducted between December 2017 to July 2019. Diagnosis of CLL was confirmed by flow cytometric immunophenenotyping using standard lymphoma panel, membrane HLA-G was determined by flow cytometry. Results: The expression of HLA-G by flowcytometry was negatively correlated with the platelet count (r = -0.516, p = 0.004) and Hb (r = -0.479, p = 0.007). The expression of HLA-G was significantly higher in CD38 positive cells (p = 0.006). The expression of HLA-G was significantly higher in Rai stage 4 compared to stage 1 & stage 2 (p = 0.001). Conclusion: It could be concluded that expression of HLA-G might represent signs of immunosuppression in CLL patients which contribute to the immune escape of tumor cells. In addition, HLA-G expression by B-CLL cells correlates significantly with the known prognostic markers of disease progression, mainly Rai clinical staging, CD38 expression and worse survival, making this parameter possibly an important prognostic factors of disease progression.

MHC Restriction: Where Are We Now?

MHC Restriction: Where Are We Now?

The murine CD94/NKG2 ligand, Qa-1b, is a high-affinity, functional ligand for the CD8αα homodimer

The immune co-receptor CD8 molecule (CD8) has two subunits, CD8α and CD8β, which can assemble into homo or heterodimers. Nonclassical (class-Ib) major histocompatibility complex (MHC) molecules (MHC-Ibs) have recently been identified as ligands for the CD8αα homodimer. This was demonstrated by the observation that histocompatibility 2, Q region locus 10 (H2-Q10) is a high-affinity ligand for CD8αα which also binds the MHC-Ib molecule H2-TL. This suggests that MHC-Ib proteins may be an extended source of CD8αα ligands. Expression of H2-T3/TL and H2-Q10 is restricted to the small intestine and liver, respectively, yet CD8αα-containing lymphocytes are present more broadly. Therefore, here we sought to determine whether murine CD8αα binds only to tissue-specific MHC-Ib molecules or also to ubiquitously expressed MHC-Ib molecules. Using recombinant proteins and surface plasmon resonance-based binding assays, we show that the MHC-Ib family furnishes multiple binding partners for murine CD8αα, including H2-T22 and the CD94/NKG2-A/B-activating NK receptor (NKG2) ligand Qa-1b We also demonstrate a hierarchy among MHC-Ib proteins with respect to CD8αα binding, in which Qa-1b > H2-Q10 > TL. Finally, we provide evidence that Qa-1b is a functional ligand for CD8αα, distinguishing it from its human homologue MHC class I antigen E (HLA-E). These findings provide additional clues as to how CD8αα-expressing cells are controlled in different tissues. They also highlight an unexpected immunological divergence of Qa-1b/HLA-E function, indicating the need for more robust studies of murine MHC-Ib proteins as models for human disease.

Plasma soluble HLA-G levels in a cohort of heart failure patients exposed to chemicals

Heart failure (HF) is a syndrome caused by structural and/or functional cardiac abnormalities, resulting in a reduced cardiac output and/or elevated intracardiac pressures. Several studies reported a crucial role of immune activation and inflammation in the chronic heart failure (HF) pathogenesis, suggesting that pro-inflammatory and anti-inflammatory mediators could be predictive markers of the HF development and/or progression. Human Leukocyte Antigen-G (HLA-G), a tolerogenic and anti-inflammatory class I non-classical major histocompatibility complex molecule, was reported to be upregulated in patients diagnosed with HF, suggesting a tentative to regulate the inflammatory condition. We evaluated soluble (s)HLA-G plasmatic levels in patients with stable chronic heart failure at baseline visit and after 6 and 12 months. The 14 bp Insertion/Deletion polymorphisms of the HLA-G gene was also analyzed. We showed that in HF subjects, sHLA-G levels were higher in NYHA class II and III subjects (mild-severe symptoms) (6.11 ± 1.15 ng/ml; 8.25 ± 2.27 ng/ml, respectively) in comparison with NYHA class I subjects (no symptoms) (2.35 ± 0.43 ng/ml) (I vs II: p = 0.0156; I vs III: p = 0.0122). Moreover, the exposure to chemicals seems to affect sHLA-G levels, with higher sHLA-G levels in exposed patients (3.36 ± 5.12 ng/ml) in comparison with unexposed subjects (2.01 ± 2.84 ng/ml). The HLA-G 3′UTR 14 bp INS/DEL polymorphism correlated with sHLA-G, with the 14 bp INS/INS genotype associated with higher sHLA-G levels during the 12 months follow-up in unexposed subjects (p = 0.008). In conclusion, these results support a correlation between sHLA-G levels, genetics and HF disease in presence of work chemical exposition.

Effects of structural changes of beta-mannosylceramide on activation of invariant natural killer T cells and stimulation of anti-tumor immunity

Abstract Invariant natural killer T cells (iNKT) are T cells that recognize a diverse repertoire of structurally distinct lipid antigens, instead of peptides, presented by the non-classical major histocompatibility complex molecule, CD1d. Agonists of iNKT cells that induce strong anti-tumor immunity in vivo include alpha-galactosylceramide (aGC) and beta-mannosylceramide (bMC). Previous studies have shown that altering the lipid structures of aGC resulted in different cytokine profiles and anti-tumor properties. In this study, we aimed to examine the effect of altering the lipid structure of bMC on cytokine profiles and anti-tumor activity. The ceramide structure of bMC was replaced with structures that had been reported to significantly alter the activity of aGC. We examined the analogues of bMC whose acyl chain was altered to a lyso, phenylfluoro, phenyl-O-phenylfluoro, or shorter unsaturated form (C20:2). Alpha-mannosylceramide (aMC) and lyso-alpha-mannosylceramide were also studied. An in vitro stimulation assay of two iNKT cell hybridomas, DN32.D3 and 24.8A, was used to determine whether the analogues can be recognized by TCRs of iNKT cells when presented by CD1d. aMC exhibited 8-fold less activity than bMC in the hybridoma assay. An in vivo CT26 lung metastasis model was used to measure the anti-tumor activity of the analogues. Surprisingly, the analogues, besides aMC, were not recognized by the iNKT hybridoma cell lines and appear to have little or no effect on tumor growth typically seen with aGC and bMC in the CT26 lung metastasis model. These results demonstrate significant differences between aGC and bMC in how the structural changes in the lipid portion affect the anti-tumor biological activity.

Casting a wider net: Immunosurveillance by nonclassical MHC molecules.

Most studies of T lymphocytes focus on recognition of classical major histocompatibility complex (MHC) class I or II molecules presenting oligopeptides, yet there are numerous variations and exceptions of biological significance based on recognition of a wide variety of nonclassical MHC molecules. These include αβ and γδ T cells that recognize different class Ib molecules (CD1, MR-1, HLA-E, G, F, et al.) that are nearly monomorphic within a given species. Collectively, these T cells can be considered “unconventional,” in part because they recognize lipids, metabolites, and modified peptides. Unlike classical MHC-specific cells, unconventional T cells generally exhibit limited T-cell antigen receptor (TCR) repertoires and often produce innate immune cell-like rapid effector responses. Exploiting this system in new generation vaccines for human immunodeficiency virus (HIV), tuberculosis (TB), other infectious agents, and cancer was the focus of a recent workshop, “Immune Surveillance by Non-classical MHC Molecules: Improving Diversity for Antigens,” sponsored by the National Institute of Allergy and Infectious Diseases. Here, we summarize salient points presented regarding the basic immunobiology of unconventional T cells, recent advances in methodologies to measure unconventional T-cell activity in diseases, and approaches to harness their considerable clinical potential.

Extended HLA-G genetic diversity and ancestry composition in a Brazilian admixed population sample: Implications for HLA-G transcriptional control and for case-control association studies

Human leukocyte antigen-G (HLA-G) is a nonclassical Major Histocompatibility Complex (MHC) molecule with immunomodulatory function and restricted tissue expression. The genetic diversity of HLA-G has been extensively studied in several populations, however, the segment located upstream −1406 has not yet been evaluated. We characterized the nucleotide variation and haplotype structure of an extended distal region (−2635), all exons and the 3′UTR segment of HLA-G by next-generation sequencing (NGS) in a sample of 335 Brazilian individuals. We detected 29 variants at the HLA-G distal promoter region, arranged into 19 haplotypes, among which we identified sites that may influence transcription factor targeting. Although the variation pattern in the distal region resembled the one observed in the conventional promoter segment, molecular signature for balancing selection was observed in the promoter segment from −1406 to −1 (Tajima’s D = 2.315, P = 0.017), but not in this distal segment (D = 1.049, P = 0.118). Furthermore, the ancestry composition of this Brazilian population sample was determined by the analysis of SNPforID 34-plex ancestry informative marker (AIM) SNP panel. The distribution of HLA-G haplotypes was ancestry-dependent, corroborating previous findings and emphasizing the importance of considering the ancestry information in association studies.

IFN-γ Regulates the Expression of MICA in Human Corneal Epithelium Through miRNA4448 and NFκB.

Major histocompatibility complex class I-related chain A (MICA), a non-classical major histocompatibility complex molecule, can stimulate or co-stimulate CD8+ T cells or natural killer (nk) cells, thus affecting cornea allograft survival. This study investigated IFN-γ regulation of MICA expression levels in human corneal epithelium by miRNA4448. MICA expression levels in human corneal epithelial cells (HCECs) stimulated with IFN-γ were detected by qRT-PCR and an enzyme-linked immunosorbent assay, and differential miRNA expression levels were measured. qRT-PCR, Western blotting, and immunofluorescence staining revealed nuclear factor kappa B (NFκB)/P65 expression in IFN-γ-treated and miRNA4448-overexpressed HCECs. A luciferase reporter assay was used to predict the interaction between NFκB and MICA. Additionally, HCECs were transfected with MICA plasmid or treated with IFN-γ and NKG2D-mAb and cocultured with NK cells and CD8+ T cells. Cell apoptosis was measured using Annexin V/PI staining. qRT-PCR detected the expression of anti-apoptosis factor Survivin and apoptosis factor Caspase 3 in MICA-transfected and IFN-γ-treated HCECs after co-culturing with NK cells and CD8+ T cells. IFN-γ (500 ng/ml, 24 h) upregulated MICA expression in HCECs in vitro. Among six differentially expressed microRNAs, miRNA4448 levels decreased the most after IFN-γ treatment. The overexpression of miRNA4448 decreased MICA expression. miRNA4448 downregulated NFκB/P65 expression in IFN-γ-induced HCEC, and it was determined that NFκB/P65 directly targeted MICA by binding to the promotor region. A coculture with NK cells and CD8+ T cells demonstrated that MICA overexpression enhanced HCEC apoptosis, which could be inhibited by NKG2D-mAb. Simultaneously, Survivin mRNA expression decreased and Caspase3 mRNA expression increased upon the interaction between MICA and NK (CD8+ T) cells in HCECs. IFN-γ enhances the expression of MICA in HCECs by modulating miRNA4448 and NFκB/P65 levels, thereby contributing to HCEC apoptosis induced by NK and CD8+ T cells. This discovery may lead to new insights into the pathogenesis of corneal allograft rejection.

To Study Plasma sHLA-G Levels of HCC Patients Showing INDEL Polymorphism and its Correlation With Response to Locoregional Therapy

Background and Aim: Human leukocyte antigen-G (HLA-G) is a class I, non-classical major histocompatibility complex molecule that participates in a tumor-driven immune escape mechanism. Ectopic expression of HLA-G is often associated with cancer. Clinical relevance of HLA-G expression and its relation with HLA-G INDEL polymorphism and therapeutic response in hepatocellular carcinoma (HCC) patient is not clear. The study was done to evaluate expression of HLA-G in HCC patients of INDEL polymorphic genotype of responder and non-responder receiving loco-regional therapy. Methods: The sHLA-G level in the sera of HCC patient receiving locoregional therapy was measured by using a commercially ELISA kit. The genotyping for INDEL polymorphism (rs371194629) was carried out by agarose gel electrophoresis of PCR amplified product and confirmation by sequencing. Therapeutic responses in HCC patient receiving locoregional therapy were assessed by mRECIST criteria. Results: The INDEL polymorphism of HCC patients (n = 40) shown 14 bp INS, INS/DEL and Del genotype in 17.5%, 62.5% and 20% cases. The level of sHLA-G in Ins, Ins/Del and Del genotype patient of responder are 334.81 ng/l, 643.65 ng/l and 586.37 ng/l respectively; whereas in responder levels were 502.21 ng/l, 584.12 ng/ml and 1414.26 ng/ml. The levels also repeated in other ELISA kit showing result similar 17.57 u/ml, 28.31 u/ml and 79.23 u/ml (Responder) and 101.54 u/ml, 35.80 u/ml and 16.84 u/ml (Non responder) in Ins, Ins/Del and Del genotype. It is clearly evident that Ins genotype of responder had shown lowest level of serum sHLA-G level. The authors have none to declare.

CD8αα intraepithelial lymphocytes arise from two main thymic precursors.

TCRαβ+ CD8αα+ intestinal intraepithelial lymphocytes (CD8αα IELs) are an abundant population of thymus-derived T cells that protect the gut barrier surface. We sought to better define the thymic IEL precursor (IELp) by analysis of their maturation, localization, and emigration. We defined two precursors among TCRβ+CD4–CD8– thymocytes using TAK1 dependence and rigorous lineage-exclusion criteria. Those IELp populations include a nascent PD-1+ population and a T-bet+ population that accumulated with age. Both gave rise to intestinal CD8αα IELs upon adoptive transfer. PD-1+ cells contained more strongly self-reactive clones and were largely classical MHC restricted. They localized to the cortex, and efficiently emigrated in an S1PR1-dependent manner. T-bet+ IELp localized to the medulla, included non-classical MHC-restricted cells and expressed NK1.1, CD103 and CXCR3. The two IELp populations further differed in TCR Vα and Vβ usage. These data provide an important foundation for understanding the biology of CD8αα IELs.

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2K(b) Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2K(b) possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules.

Structure and function of the non-classical major histocompatibility complex molecule MR1.

Polymorphic major histocompatibility complex (MHC) molecules play a central role in the vertebrate adaptive immune system. By presenting short peptides derived from pathogen-derived proteins, these "classical" MHC molecules can alert the T cell branch of the immune system of infected cells and clear the pathogen. There exist other "non-classical" MHC molecules, which while similar in structure to classical MHC proteins, are contrasted by their limited polymorphism. While the functions of many class Ib MHC molecules have still to be elucidated, the nature and diversity of antigens (if any) that some of them might present to the immune system is expected to be more restricted and might function as another approach to distinguish self from non-self. The MHC-related 1 (MR1) molecule is a member of this family of non-classical MHC proteins. It was recently shown to present unique antigens in the form of vitamin metabolites found in certain microbes. MR1 is strongly conserved genetically, structurally, and functionally through mammalian evolution, indicating its necessity in ensuring an effective immune system for members of this class. Although MR1 will be celebrating 21years this year since its discovery, most of our understanding of how this molecule functions has only been uncovered in the past decade. Herein, we discuss where MR1 is expressed, how it selectively is able to bind to its appropriate antigens and how it, then, is able to specifically activate a distinct population of T cells.

Structure of an α-Helical Peptide and Lipopeptide Bound to the Nonclassical Major Histocompatibility Complex (MHC) Class I Molecule CD1d

Mouse CD1d is a nonclassical MHC molecule able to present lipids and glycolipids to a specialized subset of T cells known as natural killer T cells. The antigens presented by CD1d have been shown to cover a broad range of chemical structures and to follow precise rules determining the potency of the antigen in the context of T cell activation. Together with lipids, initial reports suggested that CD1d can also bind and present hydrophobic peptides with (F/W)XX(I/L/M)XXW. However, the exact location of peptide binding and the molecular basis for the required motif are currently unknown. Here we present the crystal structure of the first peptide identified to bind CD1d, p99, and show that it binds in the antigen-binding groove of CD1d in a manner compatible with its presentation to T cell receptors. Interestingly, the peptide adopts an α-helical conformation, which orients the motif residues toward its deep binding groove, therefore explaining the molecular requirements for peptide binding. Moreover, we demonstrate that a lipopeptide version of the same peptide is able to bind CD1d in a similar conformation, identifying another class of molecules binding this antigen-presenting molecule.

Upregulation of Soluble HLA-G5 and HLA-G6 Isoforms in the Milder Histopathological Stages of Helicobacter pylori Infection: A Role for Subverting Immune Responses?

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.

HLA-G 14-bp Ins/Ins Genotype in Patients Harbouring Helicobacter pylori Infection: A Potential Risk Factor?

H. pylori is a potent pathogen due to its capacity to successfully evade host defence mechanisms. Despite inducing immune responses in infected individuals, sometimes these responses fail to clear the infection and the bacterium establishes a persistent infection leading to chronic inflammation. In this context, we hypothesized that human leucocyte antigen G (HLA-G), a non-classical major histocompatibility complex molecule that has the ability to regulate immune responses both in physiological and in pathological conditions, may play an important role in promoting tolerance and helping H. pylori to subvert host defence and consequently establish a chronic infection. Therefore, we evaluated the expression of HLA-G 14-bp Ins/Del polymorphism in patients harbouring H. pylori infection, as well as their relationship with histological and demographic variables, to gain a better understanding of the actual role of HLA-G and its genetic polymorphisms in bacterial infection. Sixty-eight patients with clinical symptoms suggestive of H. pylori infection were enrolled to assess HLA-G 14-bp Ins/Del polymorphism allele and genotype frequencies. After adjustment for covariates (age and gender), the odds of having the genotype Ins/Ins, compared to Del/Del, were 3.77 times greater among HP+ cases than among controls. These findings suggest that the 14-bp Ins/Ins genotype, already associated with inflammatory and autoimmune diseases as well as some viral and parasitic infections, could confer a greater risk of developing H. pylori infection.

Function of HLA-G in cancer immunoediting and its clinical benefits

Human leukocyte antigen G (HLA-G) is a nonclassical major histocompatibility complex (MHC) molecule class I expressed in immune-privileged sites and plays an essential role in the development of maternal tolerance to genetically different fetal tissues. It was described for the first time with its clinical applications by Edgardo D. Carosella and his team at the Saint-Louis Hospital. It is predominantly expressed by the cytotrophoblast, while ectopic expression is observed in certain situations, such as tumor cells. In light of the well documented immunotolerant function of HLA-G, we will focus on the role of this molecule in the escape of tumor cells from different immune cells, its expression in cancers of distinct histology and the use of soluble HLA-G in diagnosis or as pronostic factor in order to detect tumors and to control disease stage, furthermore its use as a novel therapeutic target in cancer.

HLA-G Is Differentially Expressed in Thyroid Tissues

HLA-G is a nonclassical major histocompatibility complex molecule that has well-recognized immunomodulatory properties. The expression of HLA-G in tumor cells has been considered to be detrimental, permitting tumor spreading and decreased survival. We evaluated the expression of HLA-G in histologically normal thyroid tissue, goiter, and benign and malignant thyroid tumors, and studied the relationship between HLA-G expression and patient clinical variables. The immunohistochemistry expression of HLA-G was performed on 72 specimens of papillary thyroid carcinoma (PTC), 19 follicular thyroid carcinomas (FTC), 22 follicular adenomas (FA), 22 colloid goiters (CG), and 14 histologically normal thyroid glands (NT). The percentage of HLA-G staining was graded from absent (-) to intense (+++). HLA-G was faintly expressed in areas of hyperplasia in NT and CG. In PTC, FTC, and FA, the percentage of cell staining was significantly higher than in NT and CG (p<0.001 for each comparison). The tumor area with HLA-G expression was greater in FTC (p=0.0059) and PTC (p=0.0330) compared to FA. According to the magnitude of HLA-G staining, PTC tumors >1 cm exhibited increased HLA-G staining when compared to smaller tumors (p=0.03). Aggressive histologic subtypes of PTC have a higher median stained tumor area. No association was found between HLA-G expression and tumoral staging or patient disease-free survival. The gradual increase of HLA-G expression from hyperplasia to carcinomas, and the association of strong HLA staining with some variables implicated in poor prognosis corroborate the unfavorable role of HLA-G in tumor thyroid cells, inhibiting cytotoxic immune system cells and facilitating tumor evasion and progression.