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Upregulation of HLA-Class I and II in Placentas Diagnosed with Villitis of Unknown Etiology.

ABSTRACT: The placenta utilizes many mechanisms to protect the haploidentical fetus from recognition by the maternal immune system. However, in cases of villitis of unknown etiology (VUE), maternal lymphocytes gain access into the placenta, causing significant health risks for the fetus. Evidence suggests that VUE is a rejection response between the mother and the haploidentical fetus. Therefore, we profiled human leukocyte antigen (HLA), an important predictor of transplant rejection, in VUE using placental tissue from ten patients with VUE and ten gestational age matched controls. Placentas were stained using novel multiplexed immunofluorescence (MxIF) to investigate morphology and HLA classes I and II. Gene expression was evaluated by microarray, and where available, tissue typing of mother/baby pairs was completed to determine HLA type. MxIF demonstrated strong CD8+ T cell infiltration and HLA class I staining both the distal and stem villi of VUE placentas. Compared to controls, VUE cases had significantly higher expression of HLA class II mRNA and pathway analysis demonstrated that 40% of the differentially expressed genes in VUE are related to tissue rejection. The data suggest that VUE resembles a rejection response between the mother and the fetus. It remains unknown what initiates immune recognition and why some mothers appear to be at higher risk for developing this condition than others. Understanding this etiology will be critical for developing effective interventions or prevention strategies during pregnancy.

SUBMITTER: Enninga EAL

PROVIDER: S-EPMC7255550 | biostudies-literature |

REPOSITORIES: biostudies-literature

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HLA class II subs

Project description:HLA class II full-length submissions 30/08/2022

| PRJEB55642 | ENA

Project description:Hepatocellular carcinoma (HCC) is the second cause of death for cancer worldwide, justifying the urgent need for novel therapeutic approaches. Immunotherapeutic strategies based on triggering and/or rescuing tumor antigen-specific T cells may be promising particularly if combined together. As preliminary step toward this goal, we have investigated the expression of antigen presenting molecules (HLA class I and class II) and immune checkpoints (PD-1 and PD-L1) in 43 HCC samples from distinct patients and in HCC cell lines. While normal hepatocytes did not express HLA class I and II, HCC cells strongly upregulated HLA class I while remaining negative for HLA class II. The absence of HLA class II expression in HCC cell lines correlated with lack of expression of the HLA class II transactivator, CIITA, which could not be rescued even after interferon-gamma treatment. This was due to high methylation levels of interferon-gamma-sensitive CIITA promoter IV strongly suggesting a biologically relevant developmental silencing of HLA-II expression in liver cell lineage. HCC tumor tissues showed a variable degree of leukocyte infiltration. Infiltrating lymphocytes expressed PD-1, while PD-L1 was expressed in cells with monocyte-macrophage morphology mostly localized at the tumor margin, but not in tumor cells. De novo expression of HLA class I, instrumental for presenting tumor antigens to cytotoxic T lymphocytes, and the correct characterization of the cells expressing checkpoint inhibitors in the tumor tissue should be the ground for setting novel strategies of combined approaches of immunotherapy in HCC based on tumor peptide vaccines and anti-checkpoint inhibitor antibodies.

| S-EPMC6350839 | biostudies-literature

Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA peptidomics.

Project description:The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes.

| S-EPMC8185308 | biostudies-literature

HLA Class II analysis of human pancreatic beta cells

Project description:We interrogated the transcriptome from bulk-sorted T1D donor β-cells as compared to non-diabetic donors. We found β-cells also expressed mRNA for HLA Class II and Class II antigen presentation pathway components, but not a macrophage marker.

2019-03-01 | GSE121863 | GEO

Stoichiometry of HLA class II-invariant chain oligomers.

Project description:BACKGROUND: The HLA gene complex encodes three class II isotypes, DR, DQ, and DP. HLA class II molecules are peptide receptors that present antigens for recognition by T lymphocytes. In antigen presenting cells, the assembly of matched ? and ? subunits to heterodimers is chaperoned by invariant chain (Ii). Ii forms a homotrimer with three binding sites for class II heterodimers. The current model of class II and Ii structure states that three ?? heterodimers bind to an Ii trimer. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] We have now analyzed the composition and size of the complexes of class II and Ii using epitope tagged class II subunits and density gradient experiments. We show here that class II-Ii oligomers consist of one class II heterodimer associated with one Ii trimer, such that the DR, DQ and DP isotypes are contained within separate complexes with Ii. CONCLUSION/SIGNIFICANCE: We propose a structural model of the class II-Ii oligomer and speculate that the pentameric class II-Ii complex is bent towards the cell membrane, inhibiting the binding of additional class II heterodimers to Ii.

| S-EPMC3043101 | biostudies-literature

Ancient haplotypes of the HLA Class II region.

Project description:Allelic variation in codons that specify amino acids that line the peptide-binding pockets of HLA's Class II antigen-presenting proteins is superimposed on strikingly few deeply diverged haplotypes. These haplotypes appear to have been evolving almost independently for tens of millions of years. By complete resequencing of 20 haplotypes across the approximately 100-kbp region that spans the HLA-DQA1, -DQB1, and -DRB1 genes, we provide a detailed view of the way in which the genome structure at this locus has been shaped by the interplay of selection, gene-gene interaction, and recombination.

| S-EPMC1199539 | biostudies-literature

HLA class II locus and susceptibility to podoconiosis.

Project description:BackgroundPodoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%).MethodsWe conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls.ResultsWe found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10(-9); and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10(-8)), and suggestive associations (P<1.0×10(-5)) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis.ConclusionsAssociation between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).

| S-EPMC3350841 | biostudies-literature

NetMHCIIpan-3.0, a common pan-specific MHC class II prediction method including all three human MHC class II isotypes, HLA-DR, HLA-DP and HLA-DQ.

Project description:Major histocompatibility complex class II (MHCII) molecules play an important role in cell-mediated immunity. They present specific peptides derived from endosomal proteins for recognition by T helper cells. The identification of peptides that bind to MHCII molecules is therefore of great importance for understanding the nature of immune responses and identifying T cell epitopes for the design of new vaccines and immunotherapies. Given the large number of MHC variants, and the costly experimental procedures needed to evaluate individual peptide-MHC interactions, computational predictions have become particularly attractive as first-line methods in epitope discovery. However, only a few so-called pan-specific prediction methods capable of predicting binding to any MHC molecule with known protein sequence are currently available, and all of them are limited to HLA-DR. Here, we present the first pan-specific method capable of predicting peptide binding to any HLA class II molecule with a defined protein sequence. The method employs a strategy common for HLA-DR, HLA-DP and HLA-DQ molecules to define the peptide-binding MHC environment in terms of a pseudo sequence. This strategy allows the inclusion of new molecules even from other species. The method was evaluated in several benchmarks and demonstrates a significant improvement over molecule-specific methods as well as the ability to predict peptide binding of previously uncharacterised MHCII molecules. To the best of our knowledge, the NetMHCIIpan-3.0 method is the first pan-specific predictor covering all HLA class II molecules with known sequences including HLA-DR, HLA-DP, and HLA-DQ. The NetMHCpan-3.0 method is available at http://www.cbs.dtu.dk/services/NetMHCIIpan-3.0 .

| S-EPMC3809066 | biostudies-literature

Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas.

Project description:Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995-2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.

| S-EPMC6791452 | biostudies-literature

Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes.

Project description:Colorectal cancers (CRCs) develop on the basis of a deficient DNA mismatch repair (MMR) system in about 15% of cases. MMR-deficient CRC lesions show high-level microsatellite instability (MSI-H) and accumulate numerous mutations located at coding microsatellite loci that lead to the generation of immunogenic neopeptides. Consequently, the host's antitumoral immune response is of high importance for the course of the disease in MSI-H CRC patients. Accordingly, immune evasion mediated by impairment of HLA class I antigen presentation is frequently observed in these cancers. In this study, we aimed at a systematic analysis of alterations affecting HLA class II antigen expression in MSI-H CRC. HLA class II antigens are expressed by only two-thirds of MSI-H CRCs. The mechanisms underlying the lack of HLA class II antigens in a subset of MSI-H CRCs remain unknown. We here screened HLA class II regulatory genes for the presence of coding microsatellites and identified mutations of the essential regulator genes RFX5 in 9 (26.9%) out of 34 and CIITA in 1 (2.9%) out of 34 MSI-H CRCs. RFX5 mutations were related to lack of or faint HLA class II antigen expression (p = 0.006, Fisher's exact test). Transfection with wild-type RFX5 was sufficient to restore interferon gamma-inducible HLA class II antigen expression in the RFX5-mutant cell line HDC108. We conclude that somatic mutations of the RFX5 gene represent a novel mechanism of loss of HLA class II antigen expression in tumor cells, potentially contributing to immune evasion in MSI-H CRCs.

| S-EPMC2892639 | biostudies-literature

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