Human Leukocyte antigen-C Research Articles

HLA-C*06:02 in Danish patients with psoriasis and response to biological treatment.

Whether clinical and genetic markers can be used to differentiate patients with varying responses to different psoriasis therapies needs to be elucidated. Here, we assess whether human leukocyte antigen C (HLA-C)*06:02 is associated with response to biologics. Response to treatment was defined as a Psoriasis Area and Severity Index score of ≤2 (PASI≤ 2) after 3 months. In total, 648 patients with psoriasis initiating treatment with biologics were included; 289 were HLA-C*06:02 positive and 359 were HLA-C*06:02 negative. Patients were treated with tumor necrosis factor (TNF) inhibitors (n = 469), interleukin (IL)-12/23 inhibitors (n = 92), IL-17 inhibitors (n = 78), and IL-23 inhibitors (n = 9). Significantly more patients positive for HLA-C*06:02 achieved PASI≤ 2 compared with patients negative for HLA-C*06:02 when treated with IL-12/23 inhibitors. There was no significant difference between response in HLA-C*06:02 positive and negative patients for TNF inhibitors or IL-17 inhibitors. No analyses were conducted for IL-23 inhibitors because of the limited number of patients. The data confirm that HLA-C*06:02 may be used as a biomarker for response to anti-IL12/23 treatment.

The nuclear export protein XPO1 provides a peptide ligand for natural killer cells.

XPO1 (Exportin-1/CRM1) is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anticancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics, we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of human leukocyte antigen-C. The peptide can be endogenously processed and presented to activate NK cells specifically through this receptor. Although high XPO1 expression in cancer is commonly associated with a poor prognosis, we show that the outcome of specific cancers, such as hepatocellular carcinoma, can be substantially improved if there is concomitant evidence of NK cell infiltration. We thus identify XPO1 as a bona fide tumor antigen recognized by NK cells that offers an opportunity for a personalized approach to NK cell therapy for solid tumors.

Comprehensive genomic profiling of infiltrative follicular variant of papillary thyroid carcinoma.

Infiltrative follicular variant of papillary thyroid carcinoma (IFVPTC) exhibits nuclear characteristics typical of papillary thyroid carcinoma (PTC) but demonstrates a follicular growth pattern. The diagnosis of IFVPTC presenting with atypical nuclear features of PTC poses challenges for both preoperative cytopathology and postoperative histopathology. In such cases, molecular markers are needed to serve as diagnostic aids. Given the limited knowledge of IFVPTC's genomic features, this study aimed to characterize its genetic alterations and identify clinically relevant molecular markers. Whole-exome sequencing of 50 IFVPTC tumor-normal pairs identified single-nucleotide variants, somatic copy number alterations (sCNAs), and subclonal architecture. Key mutations were verified via polymerase chain reaction and Sanger sequencing, whereas valuable biomarkers were validated via immunohistochemistry (IHC). This study found that endogenous processes rather than exogenous mutagens dominated the shaping of the genome of IFVPTC during tumorigenesis. BRAF V600E was the only common trunk mutation and significantly mutated gene in IFVPTC. Subcloning analysis found that most IFVPTC samples harbored two or more coexisting clones. sCNA analysis revealed that human leukocyte antigen C (HLA-C) and HLA-A were significantly amplified. Subsequent IHC investigations indicated that HLA-C shows promise in averting the misclassification of challenging-to-interpret IFVPTC and invasive encapsulated follicular variant of PTC (I-EFVPTC) as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Although there were several similarities between classic PTC and IFVPTC, they differed significantly in their sCNA patterns. This study provides valuable insights into IFVPTC's genetic alterations and highlights the potential of HLA-C IHC to distinguish challenging-to-interpret IFVPTC and I-EFVPTC from NIFTP, which will enhance the understanding of its molecular features for improved diagnosis and management.

P-447 Dynamic changes in uterine natural killer cell (uNK) function across menstrual phases: Implications for implantation

Abstract Study question Does the function of uNK cells change from the proliferative stage of the menstrual cycle to the secretory phase in readiness for implantation? Summary answer During the secretory phase, uNK cells demonstrate an enhanced ability to produce cytokines indicating their importance for implantation. What is known already The abundance of uNK cells during implantation, and their secretion of trophoblast chemoattractant factors, suggests their pivotal role in placentation. uNK cells express Killer Immunoglobulin-like Receptors (KIR), which interact with Human Leukocyte Antigen-C (HLA-C) on trophoblasts, inducing cytokine production that aids trophoblast migration. It has recently been discovered that uNK cells consist of three distinct subsets, with different propensities to produce cytokines. However, the cytokine production abilities of each subset, and how this changes over the menstrual cycle, remains unexplored. Study design, size, duration A prospective cross-sectional study was conducted to compare uNK cell function between the proliferative and secretory phases of the menstrual cycle. The proliferative phase was defined as before day 14 of the menstrual cycle, and the secretory phase after this, in those with a regular 28-32 day menstrual cycle. The current data analysed is from 6 proliferative phase samples and 10 secretory phase samples however recruitment is ongoing. Participants/materials, setting, methods Endometrial samples were collected with a Pipelle biopsy from healthy fertile women attending the sexual health clinic for contraception. In the laboratory, endometrial lymphocytes were isolated and cultured with Anti-CD107a PerCP-eFlour710 (100ul/ml), Brefeldin (3ug/ml) and Monensin (2uM/ml). Cells were then stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin (2ul/ml) and incubated for 4 hours at 37 °C. Flow cytometry was employed to analyse the samples after staining with viability dye, cell surface antibodies, and intracellular markers. Main results and the role of chance In initial experiments, degranulation declined during the proliferative phase in both uNK2 and uNK3 compared to the other two phases of the menstrual cycle. There was a significant increase in the production of TNFa by uNK1 and IL-8 by uNK3 in the secretory phase compared to the proliferative phase. There were also increases in IFNg and GM-CSF production across all subsets although this did not reach significance (Statistical testing was done using Kruskal Wallis with a post-hoc Dunn test, p < 0.05). Current work explores the production of more recently identified trophoblast chemoattractants, including XCL1 and CSF1, which we would expect to increase in a similar manner. Limitations, reasons for caution Limitations include the cross-sectional nature of the study, limiting the ability to establish causation. However another study, tracking pregnancy outcomes in those with recurrent implantation failure aims to address this. Additionally, variations within menstrual phases may exist. The sample size is also a limitation which I am working to expand. Wider implications of the findings A comprehensive understanding of uNK throughout various menstrual phases holds profound implications for reproductive health. The heightened cytokine production observed during the secretory phase indicates their pivotal role in the process of implantation. This finding not only underscores their significance but also serves as a catalyst for further research. Trial registration number not applicable

An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation.

TPS2677 Background: The landscape of cancer treatment is evolving with the emergence of innovative immunotherapies. Among these, T cell receptor-engineered T cell (TCR-T) therapy has shown promise for patients with solid tumor malignancies. Targeting driver mutations, such as KRAS, may offer novel therapeutic options for patients with limited treatment options. Oncogenic driver mutations in KRAS typically involve single-base mutations at genomic hotspot locations. The KRAS isoform is mutated in 84% of RAS-driven cancers and in nearly 100% of pancreatic ductal adenocarcinoma (PDAC). The KRAS G12D mutation is the most frequent mutation in PDAC (28%), followed by colorectal cancers (12%). Despite its well-established target role in tumorigenesis, there is no FDA-approved therapy targeting the G12D variant. NT-112 is an autologous TCR-T cell therapy targeting the KRAS G12D mutation presented by HLA-C*08:02, armored by disruption of the gene encoding the transforming growth factor beta receptor type 2 (TGFBR2) in order to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Methods: This first-in-human, open label, multicenter, Phase 1, dose escalation study aims to assess the safety, identify the MTD and evaluate potential anti-tumor activities of NT-112 in subjects with solid tumors. The study will enroll up to 24 adult subjects harboring the KRAS G12D mutation that are HLA-C*08:02 positive, who exhibit progressive or recurrent disease after at least one line of standard of care treatment. Enrolled patients will undergo leukapheresis, from which, CD4 and CD8 T cells will be enriched and activated ex vivo. The genes encoding the TGFBR2 and the endogenous TCR α and β chains are knocked out from the activated T cells utilizing clustered regularly interspaced short palindromic repeats (CRISPR-Cas9). The HLA-C*08:02-restricted TCR specific to the KRAS G12D mutation is knocked-in in the TCR α locus. Subjects will undergo standard lymphodepletion followed by a single infusion of NT-112 and concurrent, daily, subcutaneous, recombinant IL-2 for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days following NT-112 infusion. Disease response will be assessed according to the RECIST v1.1 criteria. Comprehensive translational analysis will be conducted to gain insights into the mechanism of action, biomarkers associated with treatment response, and potential mechanisms of resistance. All subjects will be followed for up to 15 years. Clinical trial information: NCT06218914 .

Maternal-Fetal Compatibility in Recurrent Pregnancy Loss.

Nowadays, recurrent pregnancy loss (RPL) is an undesirable condition suffered by many patients of reproductive age. In this scenario, certain immune cell populations and molecules, involved in maternal-fetal compatibility, have emerged as factors related with the pathogenesis of RPL. Among them, uterine Natural Killer cells (uNKs) appear to be of great relevance. These cells are involved in numerous processes during pregnancy, such as the remodeling of uterine spiral arteries or the control of trophoblast invasion. These functions are regulated by the interactions that these cells establish with the extravillous trophoblast, mainly through their Killer Immunoglobulin-like Receptors (KIRs) and the Human Leukocyte Antigen-C (HLA-C) molecules expressed by the embryo. A high level of polymorphism has been reported for both molecules involved in this interaction, with some of the possible KIR-HLA-C combinations being associated with an increased risk of RPL. However, the complexity of the maternal-fetal interface goes beyond this, as other HLA molecules also appear to be related to this reproductive pathology. In this review, we will discuss the role of uNKs in pregnancy, as well as the polymorphisms and clinical implications of KIR-HLA-C binding. We will also address the involvement of other, different HLA molecules in RPL, and the current advice on the appropriate management of patients with 'immunological mismatch', thus covering the main aspects regarding the involvement of maternal-fetal compatibility in RPL.

Progesterone-mediated remodeling of the maternal-fetal interface by a PGRMC1-dependent mechanism

Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system. Progesterone, a critical hormone during pregnancy, is known to promote immune tolerance and prevent preterm labor. However, the mechanism by which progesterone mediates these effects remains unclear. In this study, we investigated the role of the non-classical progesterone receptor membrane component 1 (PGRMC1) in progesterone signaling at the maternal-fetal interface. Using JEG3 cells, a trophoblast model cell line, we observed that progesterone stimulation increased the expression of human leukocyte antigen-C (HLA-C) and HLA-G, key molecules involved in immune tolerance. We also found that progesterone upregulated the expression of the transcription factor ELF3, which is known to regulate trophoblast-specific HLA-C expression. Interestingly, JEG3 cells lacked expression of classical progesterone receptors (PRs) but exhibited high expression of PGRMC1, a finding we confirmed in primary trophoblasts by mining sc-RNA seq data from human placenta. To investigate the role of PGRMC1 in progesterone signaling, we used CRISPR/Cas9 technology to knockout PGRMC1 in JEG3 cells. PGRMC1-deficient cells showed a diminished response to progesterone stimulation. Furthermore, we found that the progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner, suggesting that RU486 acts as a progesterone antagonist by competing for receptor binding. Additionally, we found that RU486 inhibited cell invasion, an important process for successful pregnancy, and this inhibitory effect was dependent on PGRMC1. Our findings highlight the crucial role of PGRMC1 in mediating the immunoregulatory effects of progesterone at the maternal-fetal interface.

Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure

Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case–control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal–fetal KIR-HLA-C mismatch in patients.

Biological profile of the follicular fluid. A pilot study

BACKGROUND: One of the most important research areas in the field of reproductive medicine is the search for biochemical and immunological parameters of oocyte quality and predicting the effectiveness of assisted reproductive technology protocols.&#x0D; AIM: The aim of this study was to evaluate the expression of follicular fluid soluble human leukocyte antigen-G, human leukocyte antigen-E, human leukocyte antigen-C, progesterone-inducing blocking factor, and relaxin levels in women with reproductive disorders.&#x0D; MATERIALS AND METHODS: This prospective cohort study included 22 patients undergoing infertility treatment in a superovulation stimulation protocol using gonadotropin-releasing hormone antagonists. The inclusion criteria were age from 25 to 39 years, tubal-peritoneal factor infertility, and voluntary participation informed consent. The levels of soluble human leukocyte antigen-G, human leukocyte antigen-E, human leukocyte antigen-C, progesterone-inducing blocking factor, and relaxin in follicular fluid samples were determined on the day of transvaginal follicle puncture by enzyme immunoassay.&#x0D; RESULTS: We established an inverse correlation between the expression levels of progesterone-inducing blocking factor and relaxin (r = 0.450) in the follicular fluid, antibodies to thyroperoxidase (r = 0.649), and thyroid-stimulating hormone (r = 0.519). We also found a direct correlation between human leukocyte antigen-E parameters in the follicular fluid, age (r = 0.813) and Body Mass Index (r = 0.866), as well as between human leukocyte antigen-C expression levels and total testosterone (r = 0.960). No data were obtained on any significant correlations between the studied biomarkers and the number of received oocytes.&#x0D; CONCLUSIONS: In this comprehensive study, we were the first who found the expression levels of five different follicular fluid components, namely, soluble human leukocyte antigen-G, human leukocyte antigen-E, human leukocyte antigen-C, progesterone-inducing blocking factor, and relaxin. Such a complex assessment of the follicular fluid can allow for establishing the quality of the oocyte to predict the onset of pregnancy in an in vitro fertilization protocol.

Biologic therapies for psoriasis and eyes

Psoriasis is a systemic inflammatory disorder, manifested mainly by skin lesions, but the inflammation also may affect the joints and eye. Many comorbidities have been described in association with psoriasis, including metabolic syndrome and coronary plaques. The pathomechanism of psoriasis is multifaceted. Both genetic and immunologic aspects play a role in stimulating inflammation. Genetic susceptibility is conditioned by presence of the human leukocyte antigen-C*06:02 risk allele and the inflammatory reaction secondary to cytokines, such as tumor necrosis factor α, interleukin 17 (IL-17), IL-20, IL-23, and interferon alfa. Besides the conventional therapy of topical steroids and immunosuppressants, biologic therapies are widely used in the treatment of psoriasis, psoriatic arthritis, and coexisting uveitis. In the majority of cases, biologic therapy has a beneficial effect on uveitis, but in some cases, some of these drugs can lead to serious side effects threatening vision.

A bioinformatic approach to identify pathogenic variants for Stevens-Johnson syndrome.

Stevens-Johnson syndrome (SJS) produces a severe hypersensitivity reaction caused by Herpes simplex virus or mycoplasma infection, vaccination, systemic disease, or other agents. Several studies have investigated the genetic susceptibility involved in SJS. To provide further genetic insights into the pathogenesis of SJS, this study prioritized high-impact, SJS-associated pathogenic variants through integrating bioinformatic and population genetic data. First, we identified SJS-associated single nucleotide polymorphisms from the genome-wide association studies catalog, followed by genome annotation with HaploReg and variant validation with Ensembl. Subsequently, expression quantitative trait locus (eQTL) from GTEx identified human genetic variants with differential gene expression across human tissues. Our results indicate that two variants, namely rs2074494 and rs5010528, which are encoded by the HLA-C (human leukocyte antigen C) gene, were found to be differentially expressed in skin. The allele frequencies for rs2074494 and rs5010528 also appear to significantly differ across continents. We highlight the utility of these population-specific HLA-C genetic variants for genetic association studies, and aid in early prognosis and disease treatment of SJS.

Human leukocyte antigen-C (HLA-C) serum level as an indicator of severity among acute respiratory syndrome coronavirus patients

One of the respiratory viruses with the highest rate of dissemination, the coronavirus, sparked a global pandemic that claimed the lives of roughly six million people. As a result, various vaccinations and medications to lessen disease severity and hasten patient recovery were developed quickly. The purpose of this study was for coronavirus patients with acute lung distress to have their serum levels measured and compared to healthy controls. One hundred eighty blood samples from respiratory infections syndrome coronavirus patients between the ages of (13-80) were included in this case-control research. Results showed that human leukocyte antigen-C (HLA-C) serum concentrations were measured in patient groups compared to healthy groups. Patients with acute lung symptoms of coronavirus had higher serum levels of HLA-C, and the outcomes were contrasted using the Kruskal-Wallis. Upon testing, it was discovered that their serum levels for HLA-C showed a significant difference (P&lt; 0.05). There were▫severe corona patients without pneumonia having a level of 40.03 ng/ml, severe corona patients with pneumonia having a level of 47.93ng/ml, non-severe corona patients without pneumonia having a level of 46.83 ng/ml, non-severe corona patients with pneumonia cases having a level of 61.15 ng/ml and with controls having a level of 17.65 ng/ml, (P ≤0.001). An increase in HLA-C serum level led to contribute to the immune storm that changes immunoregulatory▫such as including reducing the number ofˑallogeneic made by mixing lymphocyteˌcultures, death of the natural killer cell and CD8+ˌT lymphocytes, and inhibition of alloreactive cytotoxic T lymphocytes (CTL) activity.

The Association between Deoxyribonucleic Acid Hypermethylation in Intron VII and Human Leukocyte Antigen-C∗07 Expression in Patients with Endometriosis.

Endometriosis, which is a common disease affecting approximately 10% of women of reproductive age, usually causes dysmenorrhea and infertility, thus seriously harming the patients' physical and mental health. However, there is a mean delay of 6.7 years between the onset of the symptoms and the surgical diagnosis of endometriosis. There is an increasing amount of evidence that suggests that epigenetic aberrations, including deoxyribonucleic acid (DNA) methylation, play a definite role in the pathogenesis of endometriosis. This study aimed to explore the noninvasive or minimally invasive biomarkers of this disease. Six patients with surgically confirmed ovarian endometriosis and six patients who received IUD implantation for contraception without endometriosis were recruited in the East Hospital of Tongji University in 2018. The genome methylation profiling of the eutopic and ectopic endometrium of ovarian endometriosis patients and normal endometrial specimens from healthy women was determined using a methylation microarray test. The test screened methylation-differentiated 5'-C-phosphate-G-3' (CpG) sites and then located the target genes affected by these sites following sequence alignment. Then, an additional 22 patients and 26 healthy controls were enrolled to further verify the difference in the selected genes between endometriosis patients and healthy women. The differential DNA methylation of the selected genes was validated via direct bisulfite sequencing and analysis of their messenger ribonucleic acid (mRNA) levels using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Fifteen differentially methylated CpG sites were found among the patients and healthy women, and five CpG sites were mapped to the introns of the human leukocyte antigen-C (HLA-C) gene; these were highly polymorphic between different HLA-C alleles and were HLA-C∗07 specific. The results indicated that the HLA-C∗07 carrier patients exhibited significantly higher DNA methylation levels at the intron VII of HLA-C compared to the HLA-C∗07 carrier healthy controls. High HLA-C∗07 mRNA levels were also observed using qRT-PCR with HLA-C∗07-specific primers, which indicated that the hypermethylation of CpG in intron VII might suppress a silencer that regulates HLA-C∗07 expressions. Deoxyribonucleic acid hypermethylation in the intron VII of the HLA-C∗07 gene appears to regulate the expression of HLA-C∗07. The aberrant DNA methylation in this region was positively correlated with the occurrence of endometriosis.

Heme oxygenase-1 inhibits the cytotoxicity of natural killer cells to acute myeloid leukemia by downregulating human leukocyte antigen-C

Background aimsRecently, immune escape has been considered as a factor leading to relapse of acute myeloid leukemia (AML). In our previous study, heme oxygenase 1 (HO-1) proved to play an essential role in the proliferation and drug resistance of AML cells. In addition, recent studies by our group have shown that HO-1 is involved in immune escape in AML. Nevertheless, the specific mechanism by which HO-1 mediates immune escape in AML remains unclear. MethodsIn this study, we found that patients with AML and an overexpression of HO-1 had a high rate of recurrence. In vitro, overexpression of HO-1 attenuated the toxicity of natural killer (NK) cells to AML cells. Further study indicated that HO-1 overexpression inhibited human leukocyte antigen-C and reduced the cytotoxicity of NK cells to AML cells, leading to AML relapse. Mechanistically, HO-1 inhibited human leukocyte antigen-C expression by activating the JNK/C-Jun signaling pathway. ResultsIn AML, HO-1 inhibits cytotoxicity of NK cells by inhibiting the expression of HLA-C, thus causing immune escape of AML cells. ConclusionsNK cell-mediated innate immunity is important for the fight against tumors, especially when acquired immunity is depleted and dysfunctional, and the HO-1/HLA-C axis can induce functional changes in NK cells in AML. Anti-HO-1 treatment can promote the antitumor effect of NK cells and may play an important role in the treatment of AML.

Correlation between gene polymorphisms of killer cell immunoglobulin-like receptors and their ligands and Graves' disease

Objective: To explore the relationship between gene polymorphism of killer cell immunoglobulin-like receptor (KIR) and its ligand-specific human leukocyte antigen C (HLA-C) and Graves' disease (GD). Methods: Case-control study. A total of 118 unrelated GD patients (GD group) admitted to Shandong Provincial Hospital from January 2011 to December 2017 and 108 age-and sex-matched healthy controls (healthy control group) were included. The KIR genotype and its ligand HLA-C allele were detected by polymerase chain reaction sequence-specific primers (PCR-SSP). The distribution of KIR/HLA-C gene combination in GD patients and control population was analyzed to explore its association with the occurrence of GD. Results: In GD group, there were 29 males and 89 females, aged (38±14) years. In the healthy control group, there were 28 males and 80 females, aged (37±13) years. Compared with the healthy control group, the occurrence frequency of HLA-Cw01 was higher in GD group[36.4%(43/118) vs 18.5%(20/108), P=0.003], and the occurrence frequency of HLA-Cw03 and HLA-Cw06 was lower in GD group[11.9%(14/118) vs 39.8%(43/108), P<0.001; 9.3%(11/118) vs 18.5%(20/108), P=0.045]. The frequency of KIR2DL1/HLA-C2 gene combination in GD group was lower than that in control group [17.8%(21/118) vs 34.3%(37/108), P=0.005]. Logistic regression analysis showed that KIR2DL1/HLA-C2 gene combination was a protective factor for GD occurrence (OR=0.308, 95%CI: 0.126-0.752, P=0.010). Conclusions: The polymorphism of KIR/HLA-C gene is related to GD. The low expression of KIR2DL1/HLA-C2 in GD patients may be a protective factor for GD.

KIR signaling is regulated by electrostatic interaction of its cytosolic tail with the plasma membrane despite being neutral polyampholyte

Many receptors signal upon phosphorylation of tyrosine-based motifs in their cytosolic tail, with intrinsic disorder as a common feature. Studies on CD3ζ and CD3ε tails, which are disordered and polybasic, suggested regulation of phosphorylation through accessibility of tyrosines, governed by electrostatic interactions with membrane anionic lipids. We noticed characteristics of intrinsic disorder and previously unappreciated features in tyrosine-based motif-bearing cytosolic tails of many, especially, inhibitory receptors. They are neutral or acidic polyampholytes, with acidic and basic residues linearly segregated. To explore roles of these electrostatic features, we studied inhibitory killer-cell immunoglobulin-like receptor (KIR). Its cytosolic tail is a disordered neutrally charged polyampholyte, wherein juxtamembrane and membrane distal stretches are basic, and the intervening stretch is acidic. Despite lacking net charge, it interacted electrostatically with the plasma membrane. The juxtamembrane stretch was crucial for overall binding, which sequestered tyrosines in the lipid bilayer and restrained their constitutive phosphorylation. Human leukocyte antigen-C ligand binding to KIR released its tail from the plasma membrane to initiate signaling. Tail release occurred independently of KIR polymerization, clustering, or tyrosine phosphorylation, but required acidic residues of the acidic stretch. Tail interaction with the plasma membrane dictated signaling strength of KIR. These results revealed an electrostatic protein-lipid interaction that is unusual in being governed by segregated clusters of acidic and basic residues in polyampholytic disordered region of protein. In contrast to previously known, segregated distribution of oppositely charged residues made both binding and unbinding modules inherent to receptor tail, which could make the interaction an independent signaling switch.

Killer Cell Immunoglobulin-like Receptors (KIR) and Human Leucocyte Antigen C (HLA-C) Increase the Risk of Long-Term Chronic Liver Graft Rejection.

Chronic liver rejection (CR) represents a complex clinical situation because many patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors/Class I Human Leukocyte Antigens (KIR/HLA-I) interactions allow for predicting Natural Killer (NK) cell alloreactivity and influence the acute rejection of liver allograft. However, its meaning in CR liver graft remains controversial. KIR and HLA genotypes were studied in 513 liver transplants using sequence-specific oligonucleotides (PCR-SSO) methods. KIRs, human leucocyte antigen C (HLA-C) genotypes, KIR gene mismatches, and the KIR/HLA-ligand were analyzed and compared in overall transplants with CR (n = 35) and no-chronic rejection (NCR = 478). Activating KIR (aKIR) genes in recipients (rKIR2DS2+ and rKIR2DS3+) increased CR compared with NCR groups (p = 0.013 and p = 0.038). The inhibitory KIR (iKIR) genes in recipients rKIR2DL2+ significantly increased the CR rate compared with their absence (9.1% vs. 3.7%, p = 0.020). KIR2DL3 significantly increases CR (13.1% vs. 5.2%; p = 0.008). There was no influence on NCR. CR was observed in HLA-I mismatches (MM). The absence of donor (d) HLA-C2 ligand (dC2−) ligand increases CR concerning their presence (13.1% vs. 5.6%; p = 0.018). A significant increase of CR was observed in rKIR2DL3+/dC1− (p = 0.015), rKIR2DS4/dC1− (p = 0.014) and rKIR2DL3+/rKIR2DS4+/dC1− (p = 0.006). Long-term patient survival was significantly lower in rKIR2DS1+rKIR2DS4+/dC1− at 5–10 years post-transplant. This study shows the influence of rKIR/dHLA-C combinations and aKIR gene-gene mismatches in increasing CR and KIR2DS1+/C1-ligands and the influence of KIR2DS4+/C1-ligands in long-term graft survival.

Impact of Micropolymorphism Outside the Peptide Binding Groove in the Clinically Relevant Allele HLA-C*14 on T Cell Responses in HIV-1 Infection.

ABSTRACTThere is increasing evidence for the importance of human leukocyte antigen C (HLA-C)-restricted CD8+ T cells in HIV-1 control, but these responses are relatively poorly investigated. The number of HLA-C-restricted HIV-1 epitopes identified is much smaller than those of HLA-A-restricted or HLA-B-restricted ones. Here, we utilized a mass spectrometry-based approach to identify HIV-1 peptides presented by HLA-C*14:03 protective and HLA-C*14:02 nonprotective alleles. We identified 25 8- to 11-mer HLA-I-bound HIV-1 peptides from HIV-1-infected HLA-C*14:02+/14:03+ cells. Analysis of T cell responses to these peptides identified novel 6 T cell epitopes targeted in HIV-1-infected HLA-C*14:02+/14:03+ subjects. Analyses using HLA stabilization assays demonstrated that all 6 epitope peptides exhibited higher binding to and greater cell surface stabilization of HLA-C*14:02 than HLA-C*14:03. T cell response magnitudes were typically higher in HLA-C*14:02+ than HLA-C*14:03+ individuals, with responses to the Pol KM9 and Nef epitopes being significantly higher. The results show that HLA-C*14:02 can elicit stronger T cell responses to HIV-1 than HLA-C*14:03 and suggest that the single amino acid difference between these HLA-C14 subtypes at position 21, outside the peptide-binding groove, indirectly influences the stability of peptide-HLA-C*14 complexes and induction/expansion of HIV-specific T cells. Taken together with a previous finding that KIR2DL2+ NK cells recognized HLA-C*14:03+ HIV-1-infected cells more than HLA-C*14:02+ ones, the present study indicates that these HLA-C*14 subtypes differentially impact HIV-1 control by T cells and NK cells.IMPORTANCE Some human leukocyte antigen (HLA) class I alleles are associated with good clinical outcomes in HIV-1 infection and are called protective HLA alleles. Identification of T cell epitopes restricted by protective HLA alleles can give important insight into virus-immune system interactions and inform design of immune-based prophylactic/therapeutic strategies. Although epitopes restricted by many protective HLA-A/B alleles have been identified, protective HLA-C alleles are relatively understudied. Here, we identified 6 novel T cell epitopes presented by both HLA-C*14:02 (no association with protection) and HLA-C*14:03 (protective) using a mass spectrometry-based immunopeptidome profiling approach. We found that these peptides bound to and stabilized HLA-C*14:02 better than HLA-C*14:03 and observed differences in induction/expansion of epitope-specific T cell responses in HIV-infected HLA-C*14:02+ versus HLA-C*14:03+ individuals. These results enhance understanding of how the microstructural difference at position 21 between these HLA-C*14 subtypes may influence cellular immune responses involved in viral control in HIV-1 infection.

Potential Differences in the Cardiometabolic Risk Profile of Patients with Psoriatic Disease according to Their HLA-C∗06 Status.

The human leukocyte antigen-C∗06 (HLA-C∗06, formerly HLA-Cw6) is the main genetic biomarker in psoriatic disease. It has been related to several phenotypic traits in psoriatic disease, but its role in relation to cardiometabolic comorbidities is unknown at present. Here, we analyze the potential connections between this biomarker and the cardiometabolic profile of these patients. We carried out a cross-sectional observational study including 400 patients recruited at a single university hospital. Clinical and classical cardiometabolic factors were compared between HLA-C∗06-positive and HLA-C∗06-negative individuals (OR with 95% CI). Multivariate regression analyses were carried out to check for disease traits associated with different cardiometabolic risk factors. The study population included 215 men (53.8%) and 185 women (46.2%), mean age of 46 ± 15 years, and an average disease evolution of 17 ± 12.6 years. Ninety-three (23.3%) patients met CASPAR criteria for psoriatic arthritis. HLA-C∗06 carriers (n: 160, 40%) showed an earlier age at disease onset, psoriasis family history, and more severe skin disease (type I disease). After correcting for age, sex, and disease duration, they also showed less hypertension (13.8% vs. 24.2%, OR 0.7 (95% CI: 0.42-0.78), p = 0.025), lower waist circumference (94.4 ± 13.7 vs. 98.3 ± 13.8 cm), and lower BMI (27 ± 4.4 vs. 28.1 ± 4.8, p < 0.05). We confirmed the well-known association between HLA-C∗06 and type I psoriatic disease. As a novel finding, patients carrying HLA-C∗06 showed a better cardiometabolic profile. In any case, these findings need further confirmation.

Nail Involvement as a Predictor of Differential Treatment Effects of Secukinumab Versus Ustekinumab in Patients with Moderate to Severe Psoriasis

IntroductionPatients with plaque psoriasis may experience varying levels of treatment response to different biologics, based on phenotypic characteristics and underlying genetic factors. Nail psoriasis is a common manifestation of psoriasis (approx. 50% of patients) and has been linked to the human leukocyte antigen-C*0602 (HLA-C*0602) allele, which in turn has been associated with differential treatment responses to certain drugs. Here we investigate whether nail involvement in patients with psoriasis can predict differential skin responses to two biologics with different modes of action, namely secukinumab (anti-interleukin-17A) and ustekinumab (anti-interleukin-12/23), to ultimately guide treatment choice.MethodsData were pooled from the CLEAR and CLARITY studies and stratified post hoc by nail involvement status at baseline. Psoriasis Area and Severity Index (PASI) 75 and 90 responses over 52 weeks and absolute PASI ≤ 3, ≤ 1, and 0 values at weeks 16 and 52, were assessed.ResultsBased on the medical history, 30.4% (269/886) of the patients in the secukinumab arm and 29.7% (265/891) of patients in the ustekinumab arm presented with nail involvement. Nail involvement status had little to no impact on the efficacy of secukinumab, as comparable responses were achieved for patients with and without nail involvement in terms of PASI 75/90, ≤ 3, and 0 responses; slightly lower PASI ≤ 1 reponses were achieved in patients with nail involvement. In the ustekinumab arm, patients with nail involvement achieved lower responses across all endpoints.ConclusionsThese findings indicate that nail involvement can serve as an observable prognostic factor for efficacy in skin psoriasis treatment and guide the choice between secukinumab and ustekinumab.Trial RegistrationCLEAR: NCT02074982; CLARITY: NCT02826603.