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Background: HIV-1-associated neurocognitive disorders (HAND) in stable patients undergoing antiretroviral therapy (ART) may result from ongoing immune dysregulation and chronic inflammation. A contributing factor may result from the unstable HLA class I allele, HLA-C*07. Objective: To assess the genetic profile of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigens (HLA), and immune activation or senescence markers and their association with HAND in stable HIV-1 patients receiving ART. Methods: An observational cross-sectional study was carried out with 96 patients with asymptomatic or symptomatic HAND. HLA and KIR as well as immune activation/senescence biomarkers in peripheral blood cells were assessed by SSO-Luminex typing and flow cytometry, respectively. Results: HLA-C*07 is associated with symptomatic HAND. The frequency of two copies of HLA-C*07 was higher in patients with symptomatic than with asymptomatic HAND (12.0 vs. 2.2%, ρ < 0.001). The percentage of senescent CD8+CD28- T-cells was higher in patients with two copies of HLA-C*07 (ρ < 0.05). In patients with symptomatic HAND, the percentages of non-senescent CD8+CD28+ T cells were inversely proportional to the number of copies of the HLA-C*07 (ρ < 0.05). Conclusion: Patients with symptomatic HAND showed a higher frequency of the homozygotic unstable HLA-C*07 allotype, which could be associated with neurocognitive complications. Two copies of HLA-C*07 were associated with immune senescent T lymphocyte profiles characterized by the loss of CD28 expression. [ABSTRACT FROM AUTHOR]

The HLA genes are associated with various autoimmune pathologies, with the control of the immune response also being significant in organs and cells transplantation. The aim of the study is to identify the HLA-A, HLA-B, and HLA-C alleles frequencies in the analyzed Romanian cohort. We performed HLA typing using next-generation sequencing (NGS) in a Romanian cohort to estimate class I HLA allele frequencies up to a six-digit resolution. A total of 420 voluntary donors from the National Registry of Voluntary Hematopoietic Stem Cell Donors (RNDVCSH) were included in the study for HLA genotyping. Peripheral blood samples were taken and brought to the Fundeni Clinical Institute during 2020–2021. HLA genotyping was performed using the Immucor Mia Fora NGS MFlex kit. A total of 109 different alleles were detected in 420 analyzed samples, out of which 31 were for HLA-A, 49 for HLA-B, and 29 for HLA-C. The most frequent HLA-A alleles were HLA-A*02:01:01 (26.11%), HLA-A*01:01:01 (12.5%), HLA-A*24:02:01 (11.67%), HLA-A*03:01:01 (9.72%), HLA-A*11:01:01, and HLA-A*32:01:01 (each with 8.6%). For the HLA-B locus, the most frequent allele was HLA-B*18:01:01 (11.25%), followed by HLA-B*51:01:01 (10.83%) and HLA-B*08:01:01 (7.78%). The most common HLA-C alleles were HLA-C*07:01:01 (17.36%), HLA-C*04:01:01 (13.47%), and HLA-C*12:03:01 (10.69%). Follow-up studies are ongoing for confirming the detected results. [ABSTRACT FROM AUTHOR]

The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high-level HLA-C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD-like receptor (NLR) genes, NLR family pyrin domain-containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3-deficient JEG-3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on HLA-C expression, thus implicating them in immune evasion at the maternal-fetal interface. We confirmed that NLRP2 suppresses HLA-C levels and described a unique role for NLRP7 in promoting HLA-C expression in JEG-3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine-tuned by ELF3 yet have acquired divergent functions to enable proper expression levels of HLA-C in EVT, presumably through modulating the degradation kinetics of IkBα. Targeting the ELF3-NLRP2/NLRP7-HLA-C axis may hold therapeutic potential for managing pregnancy-related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Six novel HLA‐C variants with nucleotide changes in non‐coding regions: HLA‐C*04:32:01:02, ‐C*07:01:01:142, ‐C*08:04:01:05, ‐C*12:03:01:68, ‐C*12:03:01:69 and ‐C*16:01:01:41. [ABSTRACT FROM AUTHOR]

Identification of seven new HLA alleles by next‐generation sequencing. [ABSTRACT FROM AUTHOR]

PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified "protein X". The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be "protein X" candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9's function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of PCSK9's functions through interactions of HFE and HLA-C. [ABSTRACT FROM AUTHOR]

Globally, SARS-CoV-2 has negatively impacted many lives and industries due to its rapid spread, severe outcomes, and the need for the implementation of lockdown strategies across the world. SARS-CoV-2 disease severity varies among different populations. Host genetics have been associated with various diseases, and their ability to alter disease susceptibility and severity. In addition, Human Leukocyte Antigen (HLA) expression levels and alleles vary significantly among ethnic groups, which might impact the host's response to SARS-CoV-2. Our previous study highlighted that HLA-A might have an effect on COVID-19 disease severity across ethnicities. Therefore, in this study, we aim to examine the effect of HLA-B and C expression levels on COVID-19 disease severity. To achieve this, we used real-time PCR to measure the HLA mRNA expression levels of SARS-CoV-2-infected individuals from a South African cohort and compared them across ethnic groups, disease outcomes, gender, comorbidities, and age. Our results show (1) that the effect of HLA-B mRNA expression levels was associated with differences in disease severity when we compare symptomatic vs. asymptomatic (p < 0.0001). While HLA-C mRNA expression levels were not associated with COVID-19 disease severity. (2) In addition, we observed that HLA-B and HLA-C mRNA expression levels were significantly different between South African Black individuals and South African Indian individuals (p < 0.0001, p < 0.0001). HLA-B mRNA expression levels among symptomatic South African Black individuals were significantly higher than symptomatic South African Indian individuals (p < 0.0001). In addition, the HLA-B mRNA expression levels of symptomatic South African Black individuals were significantly higher than asymptomatic South African Black individuals (p > 0.0001). HLA-C mRNA expression levels among symptomatic South African Black individuals were significantly higher than among symptomatic South African Indian individuals (p = 0.0217). (3) HLA-C expression levels were significantly different between males and females (p = 0.0052). In addition, the HLA-C expression levels of asymptomatic males are higher than asymptomatic females (p = 0.0375). (4) HLA-B expression levels were significantly different between individuals with and without comorbidities (p = 0.0009). In addition, we observed a significant difference between individuals with no comorbidities and non-communicable diseases (p = 0.0034), in particular, hypertension (p = 0.0487). (5) HLA-B expression levels were significantly different between individuals between 26–35 and 56–65 years (p = 0.0380). Our work is expected to strengthen the understanding of the relationship between HLA and COVID-19 by providing insights into HLA-B and C expression levels across ethnic populations in South Africa among COVID-19-symptomatic and asymptomatic individuals. Our results highlight that HLA-B mRNA expression levels contribute to COVID-19 severity as well as variation in ethnicities associated with COVID-19. Further studies are needed to examine the effect of HLA expression levels across various ethnic groups with contributing factors. [ABSTRACT FROM AUTHOR]

Environment and lifestyle can affect the epigenome passed down from generation to generation. A mother’s nutrition can impact the methylation levels of her offspring’s epigenome, but it’s unclear which genes may be affected by malnutrition during gestation or early development. In this study, we examined the levels of methylated GC in the promoter region of HLA-C in mothers and infants from the Kichwa community in Ecuador. To do this, we analyzed saliva samples using bisulfite DNA sequencing. While we did not observe any significant differences in the mean methylation percentages in exon 1 of HLA-C between mothers and their infants after the first two years of lactation and life, respectively, we did find that infants tended to increase their methylation level during the first two years of life, while mothers tended to decrease it after the first two years of breastfeeding. When we compared methylation levels between mothers and infants using an ANOVA/posthoc Tukey test, we found that the average methylation for the entire population was less than 3% at T1 and T2. Although there was a tendency for infants to have higher methylation levels during their first two years of life and for mothers to have lower methylation levels after the first two years of breastfeeding, the mean values were not significantly different. However, we found a significant difference when we contrasted the data using a Kruskal-Wallis test at 0.05 for T1 AND T2 (p-value: 0.0148). Specifically, mothers had an average of X̅ = 2.06% and sons had X̅ = 1.57% at T2 (p-value: 0.7227), while the average for mothers was X̅ = 1.83% and for sons X̅ =1.77%. Finally, we identified three CpG motif nucleotide positions (32–33, 43–44, and 96–97) along the 122 bp analysis of HLA-C exon one, which was found to retain methylation patterns over time and is inherited from mother to offspring. Finally, our small pilot study did not reveal significant correlations between maternal and offspring nutritional status and DNA methylation levels of HLA-C exon one.

Colorectal cancer (CRC) is the most common cause of cancer-related mortality globally. It ranks as the most common cancer among men and the third most prevalent among women in Saudi Arabia, especially in the eastern region. The immune system's response to cancer is significantly influenced by natural killer cells through their killer-cell immunoglobulin-like receptors (KIRs) interaction with human leukocyte antigen (HLA) molecules. Our research aimed to target a homogeneous ethnic group in the eastern region of Saudi Arabia, analyzing the distribution of 16 KIR genes and HLA-C1/C2 allotypes in 50 CRC patients and 63 healthy controls using the sequence-specific PCR amplification method. Findings revealed significantly lower frequencies of the 2DL2 and 3DL1 genes in CRC patients compared to controls (OR = 2.21; P = 0.04) and (OR = 7.46; P = 0.00009), respectively. Additionally, a higher prevalence of HLA-C2 was noted in CRC patients (84 %) versus controls (66.7 %) (OR = 2.26; P = 0.04). Conversely, the HLA-C1C2 combination showed a protective effect against CRC (OR = 0.38; P = 0.04). Our combinatorial analysis further identified specific gene combinations correlating with CRC risk or protection. Notably, the absence of KIR2DL2 combined with the presence of KIR2DS2 emerged as a significant risk factor, while various combinations involving KIR2DL2 and/or KIR2DS1 with HLA-C ligands were associated with either increased susceptibility or protection. The study underscores the protective role of KIR2DL2 against CRC in Saudi Arabia's eastern region and suggests that the absence of KIR2DL2, especially when KIR2DS2 is present, might increase CRC risk. This research contributes to understanding genetic influences on CRC susceptibility, emphasizing the potential of KIR and HLA interactions as biomarkers for CRC risk assessment.

Eight novel HLA class I alleles detected by next‐generation sequencing. [ABSTRACT FROM AUTHOR]

The mechanisms of immune tolerance of a mother against an antigenically foreign fetus without a concomitant loss of defense capabilities against pathogens are the factors underlying the success of a pregnancy. A significant role in human defense is played by killer immunoglobulin-like receptor (KIR) receptors, which regulate the function of the natural killer (NK) cells capable of destroying antigenically foreign cells, virus-infected cells, or tumor-lesioned cells. A special subpopulation of NK cells called uterine NK cells (uNK) is found in the uterus. Disruption of the tolerance process or overactivity of immune-competent cells can lead to immune infertility, a situation in which a woman's immune system attacks her own reproductive cells, making it impossible to conceive or maintain a pregnancy. Since the prominent role of the inflammatory response in infertility, including KIR receptors and NK cells, has been postulated, the process of antigen presentation involving major histocompatibility complex (MHC) molecules (HLA) appears to be crucial for a successful pregnancy. Proper interactions between KIR receptors on female uNK cells and HLA class I molecules, with a predominant role for HLA-C, found on the surface of germ cells, are strategically important during embryo implantation. In addition, maintaining a functional balance between activating and inhibitory KIR receptors is essential for proper placenta formation and embryo implantation in the uterus. A disruption of this balance can lead to complications during pregnancy. The discovery of links between KIR and HLA-C has provided valuable information about the complexity of maternal–fetal immune interactions that determine the success of a pregnancy. The great diversity of maternal KIR and fetal HLA-C ligands is associated with the occurrence of KIR/HLA-C combinations that are more or less favorable for reproductive success. [ABSTRACT FROM AUTHOR]

Preeclampsia is a pregnancy-induced hypertensive disorder, the pathophysiology of which includes underlying maternal cardiovascular disease, deficient spiral artery remodeling during placenta development, and inflammatory immune responses at the maternal-fetal interface. Human leukocyte antigens (HLA) are major histocompatibility complex molecules essential for the recognition of foreign antigens that is central to immune defense against pathogens and critical determinants for the immune system discriminating between self and non-self tissues, such as in transplantation. Pregnancy represents a naturally existing "transplantation", where the maternal immune system must be immunologically tolerant to the developing fetus which is 50% allogeneic. It is then unsurprising that HLA also influence normal pregnancy and pregnancy complications including preeclampsia. Here we review the role of classical and non-classical HLA molecules in influencing normal physiologic function during pregnancy and describe the association of HLA with pathophysiology in preeclampsia.

Five novel HLA‐C alleles detected by next‐generation sequencing: HLA‐C*02:02:73, ‐C*03:04:106, ‐C*06:382, ‐C*07:1114Q and ‐C*12:408. [ABSTRACT FROM AUTHOR]

The HLA genes are associated with various autoimmune pathologies, with the control of the immune response also being significant in organs and cells transplantation. The aim of the study is to identify the HLA-A, HLA-B, and HLA-C alleles frequencies in the analyzed Romanian cohort. We performed HLA typing using next-generation sequencing (NGS) in a Romanian cohort to estimate class I HLA allele frequencies up to a six-digit resolution. A total of 420 voluntary donors from the National Registry of Voluntary Hematopoietic Stem Cell Donors (RNDVCSH) were included in the study for HLA genotyping. Peripheral blood samples were taken and brought to the Fundeni Clinical Institute during 2020–2021. HLA genotyping was performed using the Immucor Mia Fora NGS MFlex kit. A total of 109 different alleles were detected in 420 analyzed samples, out of which 31 were for HLA-A, 49 for HLA-B, and 29 for HLA-C. The most frequent HLA-A alleles were HLA-A*02:01:01 (26.11%), HLA-A*01:01:01 (12.5%), HLA-A*24:02:01 (11.67%), HLA-A*03:01:01 (9.72%), HLA-A*11:01:01, and HLA-A*32:01:01 (each with 8.6%). For the HLA-B locus, the most frequent allele was HLA-B*18:01:01 (11.25%), followed by HLA-B*51:01:01 (10.83%) and HLA-B*08:01:01 (7.78%). The most common HLA-C alleles were HLA-C*07:01:01 (17.36%), HLA-C*04:01:01 (13.47%), and HLA-C*12:03:01 (10.69%). Follow-up studies are ongoing for confirming the detected results.

Objective To study the correlation between platelet transfusion efficacy and KIR receptor-HLA ligand. Methods Thirty-three leukemia patients with positive HLA antibody were tested for cross-matching with donor platelets. Platelets from suitable donors were selected for transfusion, and the 24-hour platelet corrected count increment (CCI) was used to determine the transfusion effect. KIR and ligand genotyping were performed on blood samples from patients and donors by PCR-SSP method, and the relationship between platelet transfusion effects and KIR receptor-HLA ligand was analyzed. Results In 74 occasions of platelet transfusion, 42 were ineffective and 32 were effective. When the donor had C2 gene and HLA-B Bw4-80T gene, the frequency of ineffective platelet transfusion in the recipient was 69.0% (29/42) and 52.4% (22/35), respectively, which was significantly higher than that in the effective group [25.0% (8/32) and 25.0% (8/32)]. When the donor had C1 gene, and the frequency of effective platelet transfusion in the recipient was 100.0%(32/32), which was higher than that in the ineffective group [83.3%(35/42)]. When the recipient-donor matching mode was KIR2DL1-C2 and KIR3DL1-(HLA-B Bw4-80T), the frequency of ineffective platelet transfusion was 69.0%(29/42) and 40.5%(22/42),higher than that of the effective group [25% (8/32) and 18.8% (6/32)]. When the recipient-donor matching model was KIR2DL3-C1, the rate of effective platelet transfusion in 32 patients (100.0%), which was higher than that (35 patients 83. 3%) in the ineffective group. When the mismatch mode of recipient iKIR+donor HLA ligand receptor was KIR2DL1-C2, the frequency of effective platelet transfusion in the recipient was 78.1% (25/32), which was much higher than that in the ineffective group [31.0% (13/42)]. When the mismatch mode was KIR3DL1-(HLA-B Bw4-80T), the rate of effective platelet transfusion in the recipient was 68.8% (22/32), which was higher than that in the ineffective group (42.9%, 18/42). The difference between the above groups was statistically significant(P

HLA‐C*14:152 differs from HLA‐C*14:02:01:01 by a non‐synonymous nucleotide substitution in exon 5. [ABSTRACT FROM AUTHOR]

PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9’s C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified “protein X”. The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be “protein X” candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9’s function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of PCSK9’s functions through interactions of HFE and HLA-C.

HLA-C, a gene located within the major histocompatibility complex, has emerged as a prominent target in biomedical research due to its involvement in various diseases, including cancer and autoimmune disorders; even though its recent addition to the MHC, the interaction between HLA-C and KIR is crucial for immune responses, particularly in viral infections. This review provides an overview of the structure, origin, function, and pathological implications of HLA-C in the major histocompatibility complex. In the last decade, we systematically reviewed original publications from Pubmed, ScienceDirect, Scopus, and Google Scholar. Our findings reveal that genetic variations in HLA-C can determine susceptibility or resistance to certain diseases. However, the first four exons of HLA-C are particularly susceptible to epigenetic modifications, which can lead to gene silencing and alterations in immune function. These alterations can manifest in diseases such as alopecia areata and psoriasis and can also impact susceptibility to cancer and the effectiveness of cancer treatments. By comprehending the intricate interplay between genetic and epigenetic factors that regulate HLA-C expression, researchers may develop novel strategies for preventing and treating diseases associated with HLA-C dysregulation. [ABSTRACT FROM AUTHOR]

Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan–Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40–0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50–0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37–0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35–0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32–0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations. [ABSTRACT FROM AUTHOR]

(1) Background: Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) have in common a deficient maternal adaptation to the semi-allogeneic fetus, in which killer immunoglobulin-like receptor (KIR) family expressed by natural killer (NK) cells play an important role. The aim of this study was to evaluate the influence of maternal KIR haplotype on the reproductive outcomes after single embryo transfer in IVF cycles in patients with RPL and RIF. (2) Methods: Patients with RIF and RPL who presented at Origyn Fertility Center from Iasi, Romania, were prospectively enrolled between January 2020 and December 2022. Clinical and paraclinical data was examined. Descriptive statistics and a conditional logistic regression model were used to analyze our data. (3) Results: Patients with a KIR AA haplotype had significantly more chances of miscarriage if they underwent an IVF procedure (aOR: 4.15, 95% CI: 1.39–6.50, p = 0.032) compared with those who spontaneously achieved a pregnancy. Moreover, it appeared that the same haplotype increased the chances of obtaining a pregnancy for patients who underwent an IVF procedure (aOR: 2.57, 95% CI: 0.85–6.75, p = 0.023). (4) Conclusions: Determination of KIR haplotype could be beneficial for patients with RPL or RIF in order to offer an individualized management. [ABSTRACT FROM AUTHOR]

HLA-C, a gene located within the major histocompatibility complex, has emerged as a prominent target in biomedical research due to its involvement in various diseases, including cancer and autoimmune disorders; even though its recent addition to the MHC, the interaction between HLA-C and KIR is crucial for immune responses, particularly in viral infections. This review provides an overview of the structure, origin, function, and pathological implications of HLA-C in the major histocompatibility complex. In the last decade, we systematically reviewed original publications from Pubmed, ScienceDirect, Scopus, and Google Scholar. Our findings reveal that genetic variations in HLA-C can determine susceptibility or resistance to certain diseases. However, the first four exons of HLA-C are particularly susceptible to epigenetic modifications, which can lead to gene silencing and alterations in immune function. These alterations can manifest in diseases such as alopecia areata and psoriasis and can also impact susceptibility to cancer and the effectiveness of cancer treatments. By comprehending the intricate interplay between genetic and epigenetic factors that regulate HLA-C expression, researchers may develop novel strategies for preventing and treating diseases associated with HLA-C dysregulation.

The mechanisms of immune tolerance of a mother against an antigenically foreign fetus without a concomitant loss of defense capabilities against pathogens are the factors underlying the success of a pregnancy. A significant role in human defense is played by killer immunoglobulin-like receptor (KIR) receptors, which regulate the function of the natural killer (NK) cells capable of destroying antigenically foreign cells, virus-infected cells, or tumor-lesioned cells. A special subpopulation of NK cells called uterine NK cells (uNK) is found in the uterus. Disruption of the tolerance process or overactivity of immune-competent cells can lead to immune infertility, a situation in which a woman’s immune system attacks her own reproductive cells, making it impossible to conceive or maintain a pregnancy. Since the prominent role of the inflammatory response in infertility, including KIR receptors and NK cells, has been postulated, the process of antigen presentation involving major histocompatibility complex (MHC) molecules (HLA) appears to be crucial for a successful pregnancy. Proper interactions between KIR receptors on female uNK cells and HLA class I molecules, with a predominant role for HLA-C, found on the surface of germ cells, are strategically important during embryo implantation. In addition, maintaining a functional balance between activating and inhibitory KIR receptors is essential for proper placenta formation and embryo implantation in the uterus. A disruption of this balance can lead to complications during pregnancy. The discovery of links between KIR and HLA-C has provided valuable information about the complexity of maternal–fetal immune interactions that determine the success of a pregnancy. The great diversity of maternal KIR and fetal HLA-C ligands is associated with the occurrence of KIR/HLA-C combinations that are more or less favorable for reproductive success.

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

HLA‐C*17:78 differs from HLA‐C*17:03:01:03 by one nucleotide change C>T in exon 3 (GCG>GTG). [ABSTRACT FROM AUTHOR]

The novel HLA‐C*01:273 allele, first described in a potential bone marrow donor from Brazil. [ABSTRACT FROM AUTHOR]

At position 778 (C→T) in exon 3, the new allele C*05:01:81 is distinct from C*05:01:01. [ABSTRACT FROM AUTHOR]

HLA‐C*06:364 differs from HLA‐C*06:02:01:01 by a non‐synonymous nucleotide substitution in exon 3. [ABSTRACT FROM AUTHOR]

HLA‐C*04:520, a novel HLA‐C allele, differs from HLA‐C*04:01:01 by one mismatch in exon 5. [ABSTRACT FROM AUTHOR]

IntroductionNatural killer (NK) cells are key anti-tumor effectors of the innate immunity. Phenotypic differences allow us to discriminate in between three functional stages of maturation, named immature, mature and hypermature that are distinctive in terms of receptor expression, cytokine secretion, cytotoxic properties and organ trafficking. NKs display an impressive repertoire of highly polymorphic germline encoded receptors that can be either activating, triggering the effector’s function, or inhibitory, limiting the immune response. In our study, we have investigated peripheral blood NK cells of acute myeloid leukemia (AML) patients.MethodsThe Killer Immunoglobulin-like receptors (KIRs) and the HLA-C genotypes were assessed, as HLA-C molecules are cognate antigens for inhibitory KIRs.ResultsThe AA mainly inhibitory KIR haplotype was found in a higher proportion in AML, while a striking low frequency of the 2DS3 characterized the mainly activating Bx haplotype. Flow cytometry immunophenotyping evidenced a lower overall count of NK cells in AML versus healthy controls, with lower percentages of the immature and mature subpopulations, but with a markedly increase of the hypermature NKs. The analysis of the KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, and NKG2A inhibitory receptors surface expression revealed a remarkable heterogeneity. However, an overall trend for a higher expression in AML patients could be noticed in all maturation subpopulations. Some of the AML patients with complex karyotypes or displaying a FLT3 gene mutation proved to be extreme outliers in terms of NK cells percentages or inhibitory receptors expression.DiscussionWe conclude that while the genetic background investigation in AML offers important pieces of information regarding susceptibility to disease or prognosis, it is flow cytometry that is able to offer details of finesse in terms of NK numbers and phenotypes, necessary for an adequate individual evaluation of these patients.

Due to their pivotal role in orchestrating the immune response, HLA loci were recognized as candidates for genetic association studies related to the severity of COVID‐19. Since the findings on the effects of HLA alleles on the outcome of SARS‐CoV‐2 infection remain inconclusive, we aimed to elucidate the potential involvement of genetic variability within HLA loci in the molecular genetics of COVID‐19 by classifying the articles according to different disease severity/outcomes and by conducting a systematic review with meta‐analysis. Potentially eligible studies were identified by searching PubMed, Scopus and Web of Science literature databases. A total of 28 studies with 13,073 participants were included in qualitative synthesis, while the results of 19 studies with 10,551 SARS‐CoV‐2‐positive participants were pooled in the meta‐analysis. According to the results of quantitative data synthesis, association with COVID‐19 severity or with the lethal outcome was determined for the following alleles and allele families: HLA‐A*01, HLA‐A*03, HLA‐A*11, HLA‐A*23, HLA‐A*31, HLA‐A*68, HLA‐A*68:02, HLA‐B*07:02, HLA‐B*14, HLA‐B*15, HLA‐B*40:02, HLA‐B*51:01, HLA‐B*53, HLA‐B*54, HLA‐B*54:01, HLA‐C*04, HLA‐C*04:01, HLA‐C*06, HLA‐C*07:02, HLA‐DRB1*11, HLA‐DRB1*15, HLA‐DQB1*03 and HLA‐DQB1*06 (assuming either allelic or dominant genetic model). We conclude that alleles of HLA‐A, ‐B, ‐C, ‐DRB1 and ‐DQB1 loci may represent potential biomarkers of COVID‐19 severity and/or mortality, which needs to be confirmed in a larger set of studies. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the HLA-C gene in the progression and regression of cervical lesions caused by HPV infection, the present study aimed to analyze the genetic diversity and allelic variants of HLA-C gene in women CIN 2 and CIN 3 diagnosed, comparing with those without abnormalities on cervical cytology with and without the presence of infection HPV. Materials and Methods: The study group consisted of 84 women with CIN 2 and 90 women with CIN 3; the control group had no abnormality in cervical cytology consisted of 102 women negative for the presence of the HPV and 76 women with positive HPV infection. Samples were obtained from the metropolitan region of Curitiba-PR, Brazil, aged between 15 and 45 years old. The study group was treated in the Department of Pathology of the Cervical Erasto Gaertner Hospital, Curitiba and the control group was recruited in cervical cancer prevention campaigns promoted by public entities in association with the Department of Obstetrics and Gynecology, Hospital de Clínicas, Federal University of Parana and Histocompatibility and Immunogenetics Laboratory, Department of Genetics, UFPR. The HPV detection was performed by the Hybrid Capture 2 (CH2®) methodology. The DNA was extracted from peripheral blood samples and HLA-C genotyping was performed PCR-SSOP method. Results: Using G test it was observed that alleles HLA-C* 05:01 (p = 0.0096), HLA-C * 07:01P (p = 0.0096), HLA-C*07:02 (p = 0.0024), HLA-C*12:03 (p = 0.0010), HLA-C*15:02P (p = 0.0176) and HLAC*16:01 (p = 0.0415) were significantly more frequent in the study. The homozygous genotype HLAC*04:01P/*04:01P was the most frequent, reflecting the high frequency in the population studied. Allelic variants HLA-C*05:01 (p = 0.009; OR = 4.57; 95%CI 0.5749 – 36.3774), HLA-C*07:02 (p = 0.002; OR = 11.42; 95%CI 1.5173 – 86.2209) and HLA-C*12:03 (p = 0.001; OR = 7.59; 95%CI 0.9886 – 58.3472) were more frequent in women with CIN than in women with no cytological abnormalities, positive for the presence of HPV. The presence of the HLA-C*07:02 suggests susceptibility to progression of cervical intraepithelial lesion. Conclusion: Additional studies should be conducted to assess the significance of the risk of developing CC, especially in the context of KIR ligand HLA-C interactions in order to evaluate the interaction of immune system with the development of cervical cancer response.

HLA‐C*15:255 differs from HLA‐C*15:02:01 by five nucleotide substitutions located in exons 4 and 5. [ABSTRACT FROM AUTHOR]

One of the mechanisms by which viruses can evade the host's immune system is to modify the host's DNA methylation pattern. This work aims to investigate the DNA methylation and gene expression profile of COVID-19 patients, divided into symptomatic and asymptomatic, and healthy controls, focusing on genes involved in the immune response. In this study, changes in the methylome of COVID-19 patients' upper airways cells, the first barrier against respiratory infections and the first cells presenting viral antigens, are shown for the first time. Our results showed alterations in the methylation pattern of genes encoding proteins implicated in the response against pathogens, in particular the HLA-C gene, also important for the T-cell mediated memory response. HLA-C expression significantly decreases in COVID-19 patients, especially in those with a more severe prognosis and without other possibly confounding co-morbidities. Moreover, our bionformatic analysis revealed that the identified methylation alteration overlaps with enhancers regulating HLA-C expression, suggesting an additional mechanism exploited by SARS-CoV-2 to inhibit this fundamental player in the host's immune response. HLA-C could therefore represent both a prognostic marker and an excellent therapeutic target, also suggesting a preventive intervention that conjugate a virus-specific antigenic stimulation with an adjuvant increasing the T-cell mediated memory response. [ABSTRACT FROM AUTHOR]

Proper embryo implantation depends on the tolerance of the maternal immune system to the fetus and its foreign paternal antigens. During implantation and early pregnancy, the dominant leukocytes in the uterus are uterine NK cells, expressing killer immunoglobulin-like receptors (KIR). KIRs recognize human leukocyte antigens (HLA-C) on the human trophoblast inherited from the father and mother. The antigenic peptides presented by the HLA are formed via their cleavage by endoplasmic reticulum aminopeptidases ERAP1 and ERAP2. The aim of this study was to assess the association of combined KIR genes and their HLA-C ligands, as well as ERAP1 and ERAP2 polymorphisms with recurrent implantation failure after in vitro fertilization (RIF). We tested 491 couples who underwent in vitro fertilization (IVF) and 322 fertile couples. Genotype CC rs27044 ERAP1 in female with a male's HLA-C1C1 or HLA-C1C2 protected from RIF (p/pcorr. = 0.005/0.044, OR = 0.343; p/pcorr. = 0.003/0.027, OR = 0.442, respectively). Genotype TT rs30187 ERAP1 in female with a male's HLA-C1C2 genotype increased the risk of RIF. Summarizing, in the combination of female ERAP1 and an HLA-C partner, the rs30187 C>T and rs27044 C>G polymorphisms play an important role in implantation failure. [ABSTRACT FROM AUTHOR]

The HLA genes are amongst the most polymorphic in the human genome. Alternative splicing could add an extra layer of complexity, but has not been studied extensively. Here, we applied an RNA based approach to study the influence of allele polymorphism on alternative splicing of HLA‐C in peripheral blood. RNA was isolated from these peripheral cells, converted into cDNA and amplified specifically for 12 common HLA‐C allele groups. Through subsequent sequencing of HLA‐C, we observed alternative splicing variants of HLA‐C*04 and *16 that resulted in exon 5 skipping and were co‐expressed with the mature transcript. Investigation of intron 4 sequences of HLA‐C*04 and *16 compared with other HLA‐C alleles demonstrated no effect on predicted splice sites and branch point. To further investigate if the unique polymorphic positions in exon 5 of HLA‐C*04 or *16 may facilitate alternative splicing by acting on splicing regulatory elements (SRE), in‐silico splicing analysis was performed. While the HLA‐C*04 specific SNP in exon 5 had no effect on predicted exonic SRE, the HLA‐C*16 specific exon 5 SNP did alter exonic SRE. Our findings provide experimental and theoretical support for the concept that polymorphisms within the HLA‐C alleles influence the alternative splicing of HLA‐C. [ABSTRACT FROM AUTHOR]

Background: Spondyloarthritis (SpA) is a chronic inflammatory disease characterized by enthesitis, sacroiliitis, and axial joint involvement. Although the association of HLA with SpA has been widely reported, there have been no studies of HLA type in the Indonesian population within the last 20 years. This study aims to identify the HLA type in SpA patients at Dr. Soetomo General Hospital, Indonesia. Methods: This study used a cross-sectional analytical design with samples that met the criteria for SpA according to the 2009 ASAS. The clinical scores used in this study were mSASSS, BASFI, ASDAS, and Schober. Genetic identification using PCR was performed followed by sanger sequencing to determine the HLA type in the patient. DNA sequences were aligned with BLAST, and a phylogenetic tree was created using MEGA 11. Descriptive and comparative analyzes were performed using GraphPad Prism 9. Results: This study founded four types of HLA in SpA patients at Dr. Soetomo General Hospital, that is HLA-B with six alleles; -B*2704 (12.86%), -B*2705 (1.43%), -B*2706 (1.43%), -B*1802 (4.28%), -B*57v (1.43%), -B*35 (2.86%), HLA - C (21.43%), and HLA - K (52.83%). Clinical scoring of HLA-C and HLA-K indicated severe and progressive disease activity. The HLA-K had the highest mSASSS (26, 95% CI: 22–28), while HLA-C had the highest BASFI score (60, 95% CI: 55–68), the lowest Schober score (12, 95% CI: 10–14), and the shortest duration of illness (22, 95% CI: 12–36). There is no significant difference in the ASDAS score among types. Conclusions: The most common HLA types found in SpA patients at Dr. Soetomo were HLA-C and HLA-K, with the most progressive disease activity indicated by poor mSASSS, BASFI, ASDAS, and Schober scores with a short duration of illness.

Discovery of a novel HLA class I allele, HLA-C*12:424, identified using two NGS methods., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-C*14:153 differs from HLA-C*14:02:01:01 by a non-synonymous nucleotide substitution in exon 2., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One of the mechanisms by which viruses can evade the host’s immune system is to modify the host’s DNA methylation pattern. This work aims to investigate the DNA methylation and gene expression profile of COVID-19 patients, divided into symptomatic and asymptomatic, and healthy controls, focusing on genes involved in the immune response. In this study, changes in the methylome of COVID-19 patients’ upper airways cells, the first barrier against respiratory infections and the first cells presenting viral antigens, are shown for the first time. Our results showed alterations in the methylation pattern of genes encoding proteins implicated in the response against pathogens, in particular the HLA-C gene, also important for the T-cell mediated memory response. HLA-C expression significantly decreases in COVID-19 patients, especially in those with a more severe prognosis and without other possibly confounding co-morbidities. Moreover, our bionformatic analysis revealed that the identified methylation alteration overlaps with enhancers regulating HLA-C expression, suggesting an additional mechanism exploited by SARS-CoV-2 to inhibit this fundamental player in the host’s immune response. HLA-C could therefore represent both a prognostic marker and an excellent therapeutic target, also suggesting a preventive intervention that conjugate a virus-specific antigenic stimulation with an adjuvant increasing the T-cell mediated memory response.

The novel HLA‐C*15:274 allele, first described in a potential bone marrow donor from Brazil. [ABSTRACT FROM AUTHOR]

The novel allele HLA‐C*12:351Q differs from HLA‐C*12:02:02:01 by a single nucleotide deletion in exon 5. [ABSTRACT FROM AUTHOR]

The novel allele HLA‐C*07:02:147 differs from HLA‐C*07:02:01:01 by one synonymous nucleotide substitution in exon 2. [ABSTRACT FROM AUTHOR]

The phenotypic identification of different NK cell subsets allows more in‐depth characterization of KIR repertoire and function, which are of potential interest in KIR and disease association studies. KIR genes are highly polymorphic, but a great homology exists among the various sequences and few monoclonal antibodies (mAbs) specifically recognize a single KIR. This is the case of HP‐DM1 which was demonstrated by analysis of cell transfectants and epitope mapping to be exclusively KIR2DL1‐specific, covering all allotypes identified to date, except for KIR2DL1*022 and *020, and also to react with KIR2DS1*013. Here, we compared in immunofluorescence analyses the staining of HP‐DM1 with other available mAbs to precisely identify KIR2DL1+ NK cells in potential donors for αβT/B‐depleted haplo‐HSCT, with known KIR genotype. HP‐DM1 mAb was used in combination with EB6 or 11PB6 (anti‐KIR2DL1/S1 and anti‐KIR2DL3*005), 143211 (anti‐KIR2DL1/S5), and HP‐MA4 (anti‐KIR2DL1/S1/S3/S5) mAbs, allowing the accurate identification of different KIR+ NK cell subsets. These phenotypic evaluations appeared useful to dissect the expression pattern of various KIR2D in NK cells from KIR2DL3*005+ individuals, particularly if KIR2DS1 is present. HP‐DM1 mAb remarkably refined NK cell phenotyping of donors carrying KIR2DS5, either in the centromeric or telomeric region. Functional assays with KIR2DL1+/S1+/S5+ NK cells confirmed that only HP‐DM1 exclusively reacts with KIR2DL1. Finally, we demonstrated that HP‐DM1 mAb blocked KIR2DL1 recognition of C2+ HLA‐C. Altogether, the data support that HP‐DM1 is a unique reagent valuable for characterizing KIR+ NK cell subsets. [ABSTRACT FROM AUTHOR]

NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1+ individuals. Compared to 60 HIV-1- controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C+ and KIR3DL2+ NK cell sub-populations from HIV-1+ individuals was enlarged compared to HIV-1- controls. Stratification along KIR/HLA-C genotypes revealed a genotype-dependent expansion of KIR2DL1+ NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host KIR2DL/HLA-C genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1. [ABSTRACT FROM AUTHOR]

The novel HLA‐C*07:1002 allele was characterized using next‐generation sequencing technology. [ABSTRACT FROM AUTHOR]

NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1+ individuals. Compared to 60 HIV-1- controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C+ and KIR3DL2+ NK cell sub-populations from HIV-1+ individuals was enlarged compared to HIV-1- controls. Stratification along KIR/HLA-C genotypes revealed a genotype-dependent expansion of KIR2DL1+ NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host KIR2DL/HLA-C genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1.

Colorectal cancer (CRC) is the most common cause of cancer-related mortality globally. It ranks as the most common cancer among men and the third most prevalent among women in Saudi Arabia, especially in the eastern region. The immune system's response to cancer is significantly influenced by natural killer cells through their killer-cell immunoglobulin-like receptors (KIRs) interaction with human leukocyte antigen (HLA) molecules. Our research aimed to target a homogeneous ethnic group in the eastern region of Saudi Arabia, analyzing the distribution of 16 KIR genes and HLA-C1/C2 allotypes in 50 CRC patients and 63 healthy controls using the sequence-specific PCR amplification method. Findings revealed significantly lower frequencies of the 2DL2 and 3DL1 genes in CRC patients compared to controls (OR = 2.21; P = 0.04) and (OR = 7.46; P = 0.00009), respectively. Additionally, a higher prevalence of HLA-C2 was noted in CRC patients (84 %) versus controls (66.7 %) (OR = 2.26; P = 0.04). Conversely, the HLA-C1C2 combination showed a protective effect against CRC (OR = 0.38; P = 0.04). Our combinatorial analysis further identified specific gene combinations correlating with CRC risk or protection. Notably, the absence of KIR2DL2 combined with the presence of KIR2DS2 emerged as a significant risk factor, while various combinations involving KIR2DL2 and/or KIR2DS1 with HLA-C ligands were associated with either increased susceptibility or protection. The study underscores the protective role of KIR2DL2 against CRC in Saudi Arabia's eastern region and suggests that the absence of KIR2DL2, especially when KIR2DS2 is present, might increase CRC risk. This research contributes to understanding genetic influences on CRC susceptibility, emphasizing the potential of KIR and HLA interactions as biomarkers for CRC risk assessment. [ABSTRACT FROM AUTHOR]

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. • Progesterone stimulation increases the expression of human leukocyte antigen-C (HLA-C) and HLA-G. • EVT lack classical progesterone receptors (PRs) but exhibit high levels of the non-canonical progesterone receptor PGRMC1. • PGRMC1-deficient cells showed a diminished response to progesterone stimulation. • The progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner • RU486 inhibited JEG3 cell invasiveness, and this inhibitory effect was dependent on PGRMC1. [ABSTRACT FROM AUTHOR]

There is increasing evidence for the importance of human leukocyte antigen C (HLA-C)-restricted CD81 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-Ibound 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. [ABSTRACT FROM AUTHOR]