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Background: Humanized mice transplanted with CD34+ hematopoietic cells (HPCs) are broadly used to study human immune responses and infections in vivo and for testing therapies pre-clinically. However, until now, it was not clear whether interactions between the mouse major histocompatibility complexes (MHCs) and/or the human leukocyte antigens (HLAs) were necessary for human T-cell development and immune reactivity. Methods: We evaluated the long-term (20-week) human hematopoiesis and human T-cell development in NOD Scid Gamma (NSG) mice lacking the expression of MHC class I and II (NSG-DKO). Triplicate experiments were performed with HPCs obtained from three donors, and humanization was confirmed in the reference strain NOD Rag Gamma (NRG). Further, we tested whether humanized NSG-DKO mice would respond to a lentiviral vector (LV) systemic delivery of HLA-A*02:01, HLA-DRB1*04:01, human GM-CSF/IFN-α, and the human cytomegalovirus gB antigen. Results: Human immune reconstitution was detectable in peripheral blood from 8 to 20 weeks after the transplantation of NSG-DKO. Human single positive CD4+ and CD8+ T-cells were detectable in lymphatic tissues (thymus, bone marrow, and spleen). LV delivery harnessed the detection of lymphocyte subsets in bone marrow (αβ and γδ T-cells and NK cells) and the expression of HLA-DR. Furthermore, RNA sequencing showed that LV delivery increased the expression of different human reactome pathways, such as defense responses to other organisms and viruses. Conclusions: Human T-cell development and reactivity are independent of the expression of murine MHCs in humanized mice. Therefore, humanized NSG-DKO is a promising new model for studying human immune responses, as it abrogates the xenograft mouse MHC interference. [ABSTRACT FROM AUTHOR]

The Human Leukocyte Antigen (HLA) system contains a set of genes involved at many levels in the innate and adaptive immune response. Among the non-classical HLA class I genes, HLA-G stands out for the numerous studies about its pivotal role in regulating/modulating immune responses. Also, its involvement in extravillous cytotrophoblast function, viral infections, autoimmunity, and cancer has been extensively documented. The present study explores for the first time the relationship between natural alleles of HLA-G, rather than STSs, SNPs, or partial gene polymorphisms, and the development of gastric adenocarcinoma, by analyzing the genetic profile of a cohort of 40 Spanish patients with this type of tumor using DNA extracted from paired biopsies of tumoral and adjacent non-tumoral gastric tissue. Our results reveal a significant statistical relationship between the presence of the HLA-G*01:01:01 allele and the development of gastric cancer, while other common alleles such as -G*01:04 or -G*01:05N did not demonstrate a significant correlation. Studying the involvement of HLA genes in the development of many diseases is relevant to understanding their pathophysiology. However, the absence of specific mechanisms underlying these associations suggests that investigating complete HLA natural alleles' extended haplotypes or complotypes may offer a more precise and valuable approach to elucidating the association of HLA with the pathogenesis of disease. [ABSTRACT FROM AUTHOR]

This paper aims to detect a target that crosses the baseline connecting the source and the receiver in shallow-water environments, which is a special scenario for a bistatic sonar system. In such a detection scenario, an intense sound wave, known as the direct blast, propagates directly from the source to the receiver without target scattering. This direct blast usually arrives at the receiver simultaneously with the forward scattering signal and exhibits a larger intensity than the signal, posing a significant challenge for target detection. In this paper, a range-domain subspace is constructed by the horizontal distance between the source/target and each element of a horizontal linear array (HLA) when the ranges of environmental parameters are known a priori. Meanwhile, a range-domain subspace detector based on direct blast suppression (RSD-DS) is proposed for forward scattering detection. The source and the target are located at different positions, so the direct blast and the scattered signal are in different range-domain subspaces. By projecting the received data onto the orthogonal complement subspace of the direct blast subspace, the direct blast can be suppressed and the signal that lies outside the direct blast subspace is used for target detection. The simulation results indicate that the proposed RSD-DS exhibits a performance close to the generalized likelihood ratio detector (GLRD) while requiring less prior knowledge of environments (only known are the ranges of the sediment sound speed and the bottom sound speed), and its robustness to environmental uncertainties is better than that of the latter. Moreover, the proposed RSD-DS exhibits better immunity against the direct blast than the GLRD, since it can still work effectively at a signal-to-direct blast ratio (SDR) of −30 dB, while the GLRD stops working in this case. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (iDILI) by flucloxacillin presents as both cholestatic and hepatocellular injury. Its mechanistic steps are explored in the present analysis as limited data exist on the cascade of events leading to iDILI in patients with an established diagnosis assessed for causality by the Roussel Uclaf Causality Assessment Method (RUCAM). Studies with human liver microsomes showed that flucloxacillin is a substrate of cytochrome P450 (CYP) with ist preferred isoforms CYP 3A4/3A7 that toxified flucloxacillin toward 5′-hydroxymethylflucloxacillin, which was cytotoxic to human biliary epithelial cell cultures, simulating human cholestatic injury. This provided evidence for a restricted role of the metabolic CYP-dependent hypothesis. In contrast, 5′-hydroxymethylflucloxacillin generated metabolically via CYP 3A4/3A7 was not cytotoxic to human hepatocytes due to missing genetic host features and a lack of non-parenchymal cells, including immune cells, which commonly surround the hepatocytes in the intact liver in abundance. This indicated a mechanistic gap regarding the clinical hepatocellular iDILI, now closed by additional studies and clinical evidence based on HLA B*57:01-positive patients with iDILI by flucloxacillin and a verified diagnosis by the RUCAM. Naïve T-cells from volunteers expressing HLA B*57:01 activated by flucloxacillin when the drug antigen was presented by dendritic cells provided the immunological basis for hepatocellular iDILI caused by flucloxacillin. HLA B*57:01-restricted activation of drug-specific T-cells caused covalent binding of flucloxacillin to albumin acting as a hapten. Following drug stimulation, T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL25 and secreted interferon-γ and cytokines. In conclusion, cholestatic injury can be explained metabolically, while hepatocellular injury requires both metabolic and immune activation. [ABSTRACT FROM AUTHOR]

The human leukocyte antigen (HLA) system plays a pivotal role in the immune response to viral infections, mediating the presentation of viral peptides to T cells and influencing both the strength and specificity of the host immune response. Variations in HLA genotypes across individuals lead to differences in susceptibility to viral infection and severity of illness. This study uses observations from the early phase of the COVID-19 pandemic to explore how specific HLA class I molecules affect clinical responses to SARS-CoV-2 infection. By analyzing paired high-resolution HLA types and viral genomic sequences from 60 patients, we assess the relationship between predicted HLA class I peptide binding repertoires and infection severity as measured by the sequential organ failure assessment score. This approach leverages functional convergence across HLA-C alleles to identify relationships that may otherwise be inaccessible due to allelic diversity and limitations in sample size. Surprisingly, our findings show that severely symptomatic infection in this cohort is associated with disproportionately abundant binding of SARS-CoV-2 structural and non-structural protein epitopes by patient HLA-C molecules. In addition, the extent of overlap between a given patient's predicted HLA-C and HLA-A peptide binding repertoires correlates with worse prognoses in this cohort. The findings highlight immunologic mechanisms linking HLA-C molecules with the human response to viral pathogens that warrant further investigation. [ABSTRACT FROM AUTHOR]

Immunopeptidomics is the area of knowledge focused on the study of peptides assembled in the major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, which could activate the immune response via specific and selective T cell recognition. Advances in high-sensitivity mass spectrometry have enabled the detailed identification and quantification of the immunopeptidome, significantly impacting fields like oncology, infections, and autoimmune diseases. Current immunopeptidomics approaches primarily focus on workflows to identify immunopeptides from HLA molecules, requiring the isolation of the HLA from relevant cells or tissues. Common critical steps in these workflows, such as cell lysis, HLA immunoenrichment, and peptide isolation, significantly influence outcomes. A systematic evaluation of these steps led to the creation of an 'Immunopeptidome Score' to enhance the reproducibility and robustness of these workflows. This score, derived from LC-MS/MS datasets (ProteomeXchange identifier PXD038165), in combination with available information from public databases, aids in optimizing the immunopeptidome characterization process. The 'Immunopeptidome Score' has been applied in a systematic analysis of protein extraction, HLA immunoprecipitation, and peptide recovery yields across several tumor cell lines enabling the selection of peptides with optimal features and, therefore, the identification of potential biomarker and therapeutic targets. [ABSTRACT FROM AUTHOR]

Aging is an exceptionally complex process that depends on genetic, environmental, and lifestyle factors. Previous studies within the International HLA and Immunogenetics Workshop (IHIWS) component "Immunogenetics of Ageing" showed that longevity is associated with positive selection of HLA-DRB1*11- and DRB1*16-associated haplotypes, shown to be protective against diseases. Within the 18th IHIWS, we aimed to investigate the relevance of telomere length for successful aging and its association with classical HLAs. In total 957 individuals from Bulgaria, Turkey, Romania, and Poland in two age groups, elderly individuals (age 65–99 years) and ethnically matched young group (age 18–64 years), were investigated. The obtained results confirmed interpopulation differences in the distribution of HLA alleles, documented the lengths of telomeres in analyzed populations, and demonstrated significant associations of telomere length with aging as well as with the presence of some HLA class I or class II alleles. They suggest that telomere length assessment combined with HLA genotyping may help identify immunogenetic profiles associated with longevity. The associations between HLA and telomeres support the theory that HLA genes influence the aging process. However, further research is needed to clarify the biological basis of the observed relationships. [ABSTRACT FROM AUTHOR]

The WDR5/MLL1-H3K4me3 epigenetic axis is often activated in both tumor cells and tumor-infiltrating immune cells to drive various cellular responses in the tumor microenvironment and has been extensively studied in hematopoietic cancer, but its respective functions in tumor cells and immune cells in the context of tumor growth regulation of solid tumor is still incompletely understood. We report here that WDR5 exhibits a higher expression level in human pancreatic tumor tissues compared with adjacent normal pancreas. Moreover, WDR5 expression is negatively correlated with patients' response to chemotherapy or immunotherapy in human colon cancer and melanoma. However, WDR5 expression is positively correlated with the HLA level in human cancer cells, and H3K4me3 enrichment is observed at the promoter region of the HLA-A, HLA-B, and HLA-C genes in pancreatic cancer cells. Using mouse tumor cell lines and in vivo tumor models, we determined that WDR5 deficiency or inhibition significantly represses MHC I expression in vitro and in vivo in pancreatic tumor cells. Mechanistically, we determine that WDR5 deficiency inhibits H3K4me3 deposition at the MHC I (H2K) promoter region to repress MHC I (H2K) transcription. On the other hand, WDR5 depletion leads to the effective downregulation of immune checkpoints and immunosuppressive cytokines, including TGFβ and IL6, in the pancreatic tumor microenvironments. Our data determine that WDR5 not only regulates tumor cell immunogenicity to suppress tumor growth but also activates immune suppressive pathways to promote tumor immune evasion. Selective activation of the WDR5-MHC I pathway and/or selective inhibition of the WDR5–immune checkpoint and WDR5–cytokine pathways should be considered in WDR5-based epigenetic cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota". [ABSTRACT FROM AUTHOR]

Exposure to heavy metals and lifestyle factors like smoking contribute to the production of free oxygen radicals. This fact, combined with a lowered total antioxidant status, can induce even more damage in the development of ankylosing spondylitis (AS). Despite the fact that some researchers are looking for more genetic factors underlying AS, most studies focus on polymorphisms within the genes encoding the human leukocyte antigen (HLA) system. The biggest challenge is finding the effective treatment of the disease. Genetic factors and the influence of oxidative stress, mineral metabolism disorders, microbiota, and tobacco smoking seem to be of great importance for the development of AS. The data contained in this review constitute valuable information and encourage the initiation and development of research in this area, showing connections between inflammatory disorders leading to the pathogenesis of AS and selected environmental and genetic factors. [ABSTRACT FROM AUTHOR]

Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population's homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs. [ABSTRACT FROM AUTHOR]

Personalized cancer vaccines have emerged as a promising avenue for cancer treatment or prevention strategies. This approach targets the specific genetic alterations in individual patient's tumors, offering a more personalized and effective treatment option. Previous studies have shown that generalized peptide vaccines targeting a limited scope of gene mutations were ineffective, emphasizing the need for personalized approaches. While studies have explored personalized mRNA vaccines, personalized peptide vaccines have not yet been studied in this context. Pancreatic ductal adenocarcinoma (PDAC) remains challenging in oncology, necessitating innovative therapeutic strategies. In this study, we developed a personalized peptide vaccine design methodology, employing RNA sequencing (RNAseq) to identify prevalent gene mutations underlying PDAC development in a patient solid tumor tissue. We performed RNAseq analysis for trimming adapters, read alignment, and somatic variant calling. We also developed a Python program called SCGeneID, which validates the alignment of the RNAseq analysis. The Python program is freely available to download. Using chromosome number and locus data, SCGeneID identifies the target gene along the UCSC hg38 reference set. Based on the gene mutation data, we developed a personalized PDAC cancer vaccine that targeted 100 highly prevalent gene mutations in two patients. We predicted peptide-MHC binding affinity, immunogenicity, antigenicity, allergenicity, and toxicity for each epitope. Then, we selected the top 50 and 100 epitopes based on our previously published vaccine design methodology. Finally, we generated pMHC-TCR 3D molecular model complex structures, which are freely available to download. The designed personalized cancer vaccine contains epitopes commonly found in PDAC solid tumor tissue. Our personalized vaccine was composed of neoantigens, allowing for a more precise and targeted immune response against cancer cells. Additionally, we identified mutated genes, which were also found in the reference study, where we obtained the sequencing data, thus validating our vaccine design methodology. This is the first study designing a personalized peptide cancer vaccine targeting neoantigens using human patient data to identify gene mutations associated with the specific tumor of interest. [ABSTRACT FROM AUTHOR]

Background: The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. Methods: A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. Results: The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). Conclusions: The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases. [ABSTRACT FROM AUTHOR]

Heterologous vaccines, which induce immunity against several related pathogens, can be a very useful and rapid way to deal with new pandemics. In this study, the potential impact of licensed COVID-19 vaccines on cytotoxic and helper cell immune responses against Khosta-2, a novel sarbecovirus that productively infects human cells, was analyzed for the 567 and 41 most common HLA class I and II alleles, respectively. Computational predictions indicated that most of these 608 alleles, covering more than 90% of the human population, contain sufficient fully conserved T-cell epitopes between the Khosta-2 and SARS-CoV-2 spike-in proteins. Ninety percent of these fully conserved peptides for class I and 93% for class II HLA molecules were verified as epitopes recognized by CD8+ or CD4+ T lymphocytes, respectively. These results show a very high correlation between bioinformatic prediction and experimental assays, which strongly validates this study. This immunoinformatics analysis allowed a broader assessment of the alleles that recognize these peptides, a global approach at the population level that is not possible with experimental assays. In summary, these findings suggest that both cytotoxic and helper cell immune protection elicited by currently licensed COVID-19 vaccines should be effective against Khosta-2 virus infection. Finally, by being rapidly adaptable to future coronavirus pandemics, this study has potential public health implications. [ABSTRACT FROM AUTHOR]

NMDP recognizes that despite advances in hematopoietic stem cell transplantation (HSCT) and other cell therapies, not all patients have equitable access to treatment, and disparities in outcomes remain. This paper explores the recent work of NMDP to accelerate progress and expand access to more patients through transformative clinical research, particularly in the use of mismatched unrelated donors for HSCT. [ABSTRACT FROM AUTHOR]

Histocompatibility testing is pivotal in any renal transplantation workup, aimed at enhancing prospective donor recipient compatibility and improving transplant outcomes. The evolution and advancement of histocompatibility testing, particularly HLA typing, have significantly improved its precision. This study outlines the historical progression from serologic to DNA-based HLA typing, emphasizing the role of HLA proteins in immune response. Anti-HLA antibodies, targeting HLA proteins, pose challenges in renal transplantation. Monitoring and managing these antibodies are critical for renal transplant success. Complement-dependent cytotoxicity crossmatch and flow cytometry crossmatch are essential techniques for assessing donor–recipient compatibility. Panel-reactive antibody assesses antibodies against a panel of donor antigens, often HLA. Higher PRA levels (percentage) complicate donor matching, requiring specialized protocols. Virtual crossmatch evaluates recipient anti-HLA antibodies against potential donors through synthetic beads. This approach predicts crossmatch outcomes by comparing antibody profiles, offering a valuable tool for the risk assessment of renal transplantation. Despite advancements, a comprehensive understanding of alloreactive immune responses requires a combination of assays, emphasizing the importance of a multifaceted approach in histocompatibility testing. This is an attempt to compile the relevant information, providing a basis for comparison in a clear and foundational format for histocompatibility testing laboratories. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II [HLA-DR, DP and DQ]) was carried out using the Next Generation DNA Sequencing method (three fields) in 92 Thai patients with systemic sclerosis (55 dcSSc, 37 lcSSc) and 135 healthy controls (HCs). The distribution of HLA alleles in patients with dcSSc and lcSSc was compared. When compared with HCs, the AF of A*24:02:01, A*24:07:01, B*27:04:01 and B*27:06 showed an increasing trend in lcSSc patients without statistical significance. DRB1*15:02:01, DRB5*01:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01 increased significantly in dcSSc patients. DQB1*05:01:24 and DPB1*13:01:01 also increased significantly in lcSSc patients, but less significantly than in dcSSc patients. The association of DPB1*05:01:01 with lcSSc was significantly protective. HLA-A*24:02:01, B*27:06 and C*03:04:01 formed a three-locus haplotype that also constituted an eight-locus haplotype with DRB1*15:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01. There was a possibility that HLA Class I would play a role in the pathogenesis of lcSSc, while Class II played more of a role in the dcSSc in Thai patients. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless depths of complexity. In recent years, a surge of high-powered genome-wide association studies (GWASs) utilizing single nucleotide polymorphism (SNP) arrays has occurred, significantly advancing our understanding of disease pathogenesis. Additionally, advances in HLA reference panels have enabled higher resolution and more reliable imputation, allowing for finer-grained evaluation of the association between sequence variations and disease risk. However, it is essential to note that the majority of these GWASs have focused primarily on populations of Caucasian and Asian origins, neglecting underrepresented populations in Latin America and Africa. This omission not only leads to disparities in health care access but also restricts our knowledge of novel genetic variants involved in disease pathogenesis within these overlooked populations. Since the KIR and HLA haplotypes prevalent in each population are clearly modelled by the specific environment, the aim of this review is to encourage studies investigating HLA/KIR involvement in infection and autoimmune diseases, reproduction, and transplantation in underrepresented populations. [ABSTRACT FROM AUTHOR]

Hepatitis C Virus (HCV) infection represents a significant global health challenge, with its natural course largely influenced by the host's immune response. Human Leukocyte Antigen (HLA) molecules, particularly HLA class I and II, play a crucial role in the adaptive immune response against HCV. The polymorphism of HLA molecules contributes to the variability in immune response, affecting the outcomes of HCV infection. This study aims to investigate the frequency of HLA A, B, DR, and DQ alleles known to be associated with HCV clearance or persistence in a healthy Moroccan population. Conducted at the University Hospital Center Mohammed VI, Marrakech, this study spanned from 2015 to 2022 and included 703 healthy Moroccan individuals. HLA class I and II typing was performed using complement-dependent cytotoxicity and polymerase chain reaction-based methodologies. The results revealed the distinct patterns of HLA-A, B, DRB1, and DQB1 alleles in the Moroccan population. Notably, alleles linked to favorable HCV outcomes, such as HLA-DQB1*0301, DQB1*0501, and DRB1*1101, were more prevalent. Conversely, alleles associated with increased HCV susceptibility and persistence, such as HLA-DQB1*02 and DRB1*03, were also prominent. Gender-specific variations in allele frequencies were observed, providing insights into genetic influences on HCV infection outcomes. The findings align with global trends in HLA allele associations with HCV infection outcomes. The study emphasizes the role of host genetics in HCV infection, highlighting the need for further research in the Moroccan community, including HCV-infected individuals. The prevalence of certain HLA alleles, both protective and susceptibility-linked, underscores the potential for a national HLA data bank in Morocco. [ABSTRACT FROM AUTHOR]

Background/Objectives: The novel coronavirus disease 2019 (COVID-19) has led to significant morbidity and mortality among kidney transplant recipients. SARS-CoV-2 has been hypothesized to cause an unusual immunological dysregulation triggering alloimmunity and leading to graft rejection. Methods: This prospective observational cohort study assessed 321 kidney transplant recipients who had COVID-19 infection. After the infection, patients' sera were tested for the presence of anti-HLA de novo DSA and non-DSA specificities. Logistic regression analysis and a stepwise multivariable logistic regression analysis were used to analyze the independent risk factors associated with the development of antibodies, adjusting for known confounders. The variables evaluated were acute COVID-19 characteristics (i.e., presentation, and need for hospitalization), demographic characteristics (i.e., age, gender, and primary renal disease), clinical characteristics (i.e., various comorbidities), and post-COVID-19 sequelae. Results: Anti-HLA de novo DSA developed in 18.7% of patients, while anti-HLA class I and class II non-DSA antibodies developed de novo in 84 (26.3%) and 83 (25.9%) patients, respectively. The development of DSA, HLA-DQ, and HLA-DR antibodies was predicted by the history of graft rejection. Obesity appeared to be protective against the emergence of de novo DSA. De novo DSA and HLA-DR antibody formation was positively linked with intravenous immunoglobulin use, CMV-hyperimmune globulin use, and decreased doses of immunosuppression during acute infection. Better allograft function during the acute disease was a protective factor against the formation of HLA-DQ and HLA-DR antibodies. Positive predictors of de novo DSA development were graft biopsy and the reactivation of EBV after infection. Conclusions: These findings suggest that the SARS-CoV-2 virus has an immunomodulatory effect and may be associated with an increased mortality in this population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Autoimmune thyroid diseases (AITD), particularly Hashimoto's thyroiditis (HT) and Basedow–Graves disease (BGD) are diseases of global public health concern, characterized by autoimmune attacks on the thyroid gland, leading to hypothyroidism in HT and hyperthyroidism in BGD. We conducted a study between 2019 and 2021 in northwestern Transylvania (Romania) on patients with HT and with BGD compared to the control group. The aim of the study was to investigate the correlations of HLA class II alleles with AITD by identifying potential genetic susceptibility factors such as HLA-DRB1 and HLA-DQB1 genes in patients diagnosed with HT and BGD. Various molecular biology methods, including SSP-PCR low-resolution and PCR-SSO were employed to analyze DNA samples from patients and control subjects. Our study revealed the influence of the HLA-DRB1*03/*16 genotype as a genetic susceptibility factor for HT, a similar influence regarding BGD being observed for the HLA-DRB1*03 allele group, DRB1*03/*16 genotype, and the DRB1*03/DQB1*06 haplotype. The only protective factor detected in our study was the HLA-DRB1*13 allele group, for both HT and BGD. By elucidating any specific allele or genotype associations that might contribute to the development of AITD, our study can contribute to the prevention and early detection of these diseases. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) has left a devasting effect on various regions globally. Africa has exceptionally high rates of other infectious diseases, such as tuberculosis (TB), human immunodeficiency virus (HIV), and malaria, and was not impacted by COVID-19 to the extent of other continents Globally, COVID-19 has caused approximately 7 million deaths and 700 million infections thus far. COVID-19 disease severity and susceptibility vary among individuals and populations, which could be attributed to various factors, including the viral strain, host genetics, environment, lifespan, and co-existing conditions. Host genetics play a substantial part in COVID-19 disease severity among individuals. Human leukocyte antigen (HLA) was previously been shown to be very important across host immune responses against viruses. HLA has been a widely studied gene region for various disease associations that have been identified. HLA proteins present peptides to the cytotoxic lymphocytes, which causes an immune response to kill infected cells. The HLA molecule serves as the central region for infectious disease association; therefore, we expect HLA disease association with COVID-19. Therefore, in this narrative review, we look at the HLA gene region, particularly, HLA class I, to understand its role in COVID-19 disease. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease, the prevalence of which is increasing. Genetic, genomic, and epigenetic changes play a significant role in the pathogenesis of psoriasis. This review summarizes the impact of epigenetics on the development of psoriasis and highlights challenges for the future. The development of epigenetics provides a basis for the search for genetic markers associated with the major histocompatibility complex. Genome-wide association studies have made it possible to link psoriasis to genes and therefore to epigenetics. The acquired knowledge may in the future serve as a solid foundation for developing newer, increasingly effective methods of treating psoriasis. In this narrative review, we discuss the role of epigenetic factors in the pathogenesis of psoriasis. [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology. [ABSTRACT FROM AUTHOR]

Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

In this study, we aimed to investigate whether specific HLA alleles found in patients from Romania and the Republic of Moldova were associated with the severity of COVID-19 infection and its associated mortality. We analyzed the HLA alleles at the -A, -B, -C, -DRB1, and -DQB1 loci in a cohort of 130 individuals with severe and extremely severe forms of COVID-19, including 44 individuals who died. We compared these findings to a control group consisting of individuals who had either not been diagnosed with COVID-19 or had experienced mild forms of the disease. Using multivariate logistic regression models, we discovered that the B*27 and B*50 alleles were associated with an increased susceptibility to developing a severe form of COVID-19. The A*33 and C*15 alleles showed potential for offering protection against the disease. Furthermore, we identified two protective alleles (A*03 and DQB1*02) against the development of extremely severe forms of COVID-19. By utilizing score statistics, we established a statistically significant association between haplotypes and disease severity (p = 0.021). In summary, this study provides evidence that HLA genotype plays a role in influencing the clinical outcome of COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background: Middle East respiratory syndrome (MERS) is a lower respiratory tract disease caused by a beta coronavirus (CoV) called MERS-CoV, characterized by a high mortality rate. We aimed to evaluate the association between genetic variation in killer cell immunoglobulin-like receptors (KIRs) and the risk of MERS in South Koreans. Methods: KIR genes were genotyped by multiplex polymerase chain reaction with sequence-specific primers (PCR-SSP). A case-control study was performed to identify the odds ratios (OR) of KIR genes for MERS and the association of KIR genes and their ligands, human leukocyte antigens (HLA) genes. Results: KIR2DS4D and KIR3DP1F showed higher frequencies in the group of all patients infected with MERS-CoV than in the control group (p = 0.023, OR = 2.4; p = 0.039, OR = 2.7). KIR2DL1, KIR2DP1, and KIR3DP1D were significantly associated with moderate/mild (Mo/Mi) cases. KIR2DL2, KIR2DS1, and KIR3DP1F were affected in severe cases. When we investigated the association between KIR genes and their ligands in MERS patient and control groups, KIR3DL1+/Bw4(80I)+, KIR3DL1+/Bw6+, KIR3DL1+/Bw6−, KIR2DS1+/C2+, and KIR3DS+/Bw4(80I)+ were associated with MERS. KIR3DL1+/Bw6− was found in Mo/Mi cases. KIR2DS1+/C2+ and KIR2DS2+/C1+ were found in severe cases. Conclusion: Further investigations are needed to prove the various immune responses of MERS-CoV-infected cells according to variations in the KIR gene and ligand gene. A treatment strategy based on current research on the KIR gene and MERS-CoV will suggest potential treatment targets. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 caused the devastating COVID-19 pandemic, which, to date, has resulted in more than 800 million confirmed cases and 7 million deaths worldwide. The rapid development and distribution (at least in high-income countries) of various vaccines prevented these overwhelming numbers of infections and deaths from being much higher. But would it have been possible to develop a prophylaxis against this pandemic more quickly? Since SARS-CoV-2 belongs to the subgenus sarbecovirus, with its highly homologous SARS-CoV-1, we propose here that while SARS-CoV-2-specific vaccines are being developed, phase II clinical trials of specific SARS-CoV-1 vaccines, which have been in the pipeline since the early 20th century, could have been conducted to test a highly probable cross-protection between SARS-CoV-1 and SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Simple Summary: Fragments of pathogens, such as viruses and bacteria as well as cancer cells, are presented to the immune system via the major histocompatibility complex (MHC). Immunopeptidomics is a mass spectrometry-based technique that allows us to identify which peptide fragments of pathogens or aberrant mutated proteins are presented and potentially recognized by the immune system. Recent technological developments in mass spectrometry as well as sample preparation, peptide separation, and data analysis have substantially propelled the field of immunopeptidomics further and often initially were developed or incentivized for the measurement of single-cell proteomics. This perspective describes how developments in single-cell proteomics have benefitted immunopeptidomics and how further implementations could still boost sensitivity, and it will explore future directions and trends in immunopeptidomics. Immunopeptidomics, as the analysis of antigen peptides being presented to the immune system via major histocompatibility complexes (MHC), is being seen as an imperative tool for identifying epitopes for vaccine development to treat cancer and viral and bacterial infections as well as parasites. The field has made tremendous strides over the last 25 years but currently still faces challenges in sensitivity and throughput for widespread applications in personalized medicine and large vaccine development studies. Cutting-edge technological advancements in sample preparation, liquid chromatography as well as mass spectrometry, and data analysis, however, are currently transforming the field. This perspective showcases how the advent of single-cell proteomics has accelerated this transformation of immunopeptidomics in recent years and will pave the way for even more sensitive and higher-throughput immunopeptidomics analyses. [ABSTRACT FROM AUTHOR]

Associations of HLA class II alleles with genital chlamydial infection outcomes have been reported, especially HLA DQB1*06. However, the potential role of DQB1*06 in influencing reinfection risk has still not been established. The purpose of this study was to determine whether the association of DQB1*06 with chlamydia reinfection was impacted by any other nearby HLA class II variants that were also associated with reinfection. We used next-generation sequencing to map HLA class II variants spanning the HLA-DQ and -DR loci. DQB1*06 as well as DQB1*04 were confirmed as significant predictors of chlamydia reinfection, when controlling for age and percent African ancestry. SKAT analysis revealed one region each in DRB1, DRB5, DQA2, and three intergenic regions that had variants associated with reinfection. Further analyses of these variants revealed that rs112651494 within DRB5 and an intergenic SNP rs617058 in DRB1:DQA1 were significantly associated with reinfection, but this did not impact the significance of the association of DQB1*06 or DQB1*04 with reinfection. [ABSTRACT FROM AUTHOR]

Nonsyndromic biliary atresia (BA) is a rare polygenic disease, with autoimmunity, virus infection and inflammation thought to play roles in its pathogenesis. We conducted a genome-wide association study in 336 nonsyndromic BA infants and 8900 controls. Our results validated the association of rs17095355 in ADD3 with BA risk (odds ratio (OR) = 1.70, 95% confidence interval (95% CI) = 1.49–1.99; p = 4.07 × 10−11). An eQTL analysis revealed that the risk allele of rs17095355 was associated with increased expression of ADD3. Single-cell RNA-sequencing data and immunofluorescence analysis revealed that ADD3 was moderately expressed in cholangiocytes and weakly expressed in hepatocytes. Immuno-fluorescent staining showed abnormal deposition of ADD3 in the cytoplasm of BA hepatocytes. No ADD3 auto-antibody was observed in the plasma of BA infants. In the HLA gene region, no variants achieved genome-wide significance. HLA-DQB1 residue Ala57 is the most significant residue in the MHC region (OR = 1.44, 95% CI = 1.20–1.74; p = 1.23 × 10−4), and HLA-DQB1 was aberrantly expressed in the bile duct cells. GWAS stratified by cytomegalovirus (CMV) IgM status in 87 CMV IgM (+) BA cases versus 141 CMV IgM (−) BA cases did not yield genome-wide significant associations. These findings support the notion that common variants of ADD3 account for BA risk. The HLA genes might have a minimal role in the genetic predisposition of BA due to the weak association signal. CMV IgM (+) BA patients might not have different genetic risk factor profiles compared to CMV IgM (−) subtype. [ABSTRACT FROM AUTHOR]

Objectives: The prevalence of chronic kidney disease (CKD) was reported to be higher in rheumatoid arthritis (RA) patients than in normal healthy individuals. Human leukocyte antigen (HLA) was associated with RA or CKD. Few studies on the association of HLA with CKD in RA have been reported. Here, we investigated the association of HLA polymorphisms with CKD in Japanese RA patients. Methods: HLA-DRB1 genotyping was conducted in 351 Japanese RA patients with CKD (estimated glomerular filtration rate [eGFR] lower than 60 [mL/min/1.73 m2]) and 959 without CKD (eGFR equal to or higher than 60 [mL/min/1.73 m2]). Associations of allele carrier frequencies of DRB1 with CKD were examined in the RA patients. Results: There was an association of DRB1*13:02 with CKD in RA, but this did not achieve statistical significance (p = 0.0265, odds ratio [OR] 1.70, pc = 0.7412, 95% confidence interval [CI] 1.09–2.64). The DR6 serological group was associated with CKD in RA (p = 0.0008, OR 1.65, 95% CI 1.24–2.20). A gene-dosage effect of DR6 was not detected. Logistic regression analysis showed that the association of DR6 with CKD in RA was independent of clinical characteristics. Conclusions: The present study first revealed the independent predisposing association of DR6 with CKD in Japanese RA patients, although DR6 is known to be protective against RA. Our data suggest direct or indirect roles of HLA for the development of CKD in RA, but the mechanisms are not clear. [ABSTRACT FROM AUTHOR]

As the MHC-I-pathway is key to antigen presentation to cytotoxic T-cells and, therefore, recognition by the host adaptive immune system, we hypothesized that SARS-CoV-2 including its Variants of Concern (VOCs), influences MHC-I expression on epithelial cell surfaces as an immune evasion strategy. We conducted an in vitro time course experiment with the human airway epithelial cell line Calu-3 and the human colorectal adenocarcinoma cell line Caco-2. Cells were infected with SARS-CoV-2 strains non-VOC/B.1.1, Alpha/B.1.1.7, Beta/B.1.351, Gamma/P.1, and Delta/B.1.617.2. At 2, 24, 48 and 72 h post-infection we performed RT-qPCR to track viral replication. Simultaneously, we performed intracellular staining with a serum of a double-vaccinated healthy adult containing a high amount of spike protein antibody. In flow cytometry experiments, we differentiated between infected (spike protein positive) and bystander (spike protein negative) cells. To compare their HLA expression levels, cells were stained extracellularly with anti-HLA-A-IgG and anti-HLA-B,C-IgG. While HLA-A expression was stable on infected Calu-3 cells for all variants, it increased to different degrees on bystander cells in samples infected with VOCs Beta, Gamma, Delta, or non-VOC over the time course analyzed. In contrast, HLA-A levels were stable in bystander Calu-3 cells in samples infected with the Alpha variant. The upregulation of MHC-I on spike protein negative bystander cells in Calu-3 cell cultures infected with Beta, Gamma, Delta, and partly non-VOC might suggest that infected cells are still capable of secreting inflammatory cytokines like type-I interferons stimulating the MHC-I expression on bystander cells. In comparison, there was no distinct effect on HLA expression level on Caco-2 cells of any of the VOCs or non-VOC. Further investigations of the full range of immune evasion strategies of SARS-CoV-2 variants are warranted. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae contributes to a range of infections, including meningitis, pneumonia, otitis media, and sepsis. Infections by this bacterium have been associated with the phenomenon of molecular mimicry, which, in turn, may contribute to the induction of autoimmunity. In this study, we utilized a bioinformatics approach to investigate the potential for S. pneumoniae to incite autoimmunity via molecular mimicry. We identified 13 S. pneumoniae proteins that have significant sequence similarity to human proteins, with 11 of them linked to autoimmune disorders such as psoriasis, rheumatoid arthritis, and diabetes. Using in silico tools, we predicted the sequence as well as the structural homology among these proteins. Database mining was conducted to establish links between these proteins and autoimmune disorders. The antigenic, non-allergenic, and immunogenic sequence mimics were employed to design and validate an immune response via vaccine construct design. Mimic-based vaccine construct can prove effective for immunization against the S. pneumoniae infections. Immune response simulation and binding affinity was assessed through the docking of construct C8 to human leukocyte antigen (HLA) molecules and TLR4 receptor, with promising results. Additionally, these mimics were mapped as conserved regions on their respective proteins, suggesting their functional importance in S. pneumoniae pathogenesis. This study highlights the potential for S. pneumoniae to trigger autoimmunity via molecular mimicry and the possibility of vaccine design using these mimics for triggering defense response. [ABSTRACT FROM AUTHOR]

Background: After the start of the worldwide COVID-19 vaccination campaign, there were increased reports of autoimmune diseases occurring de novo after vaccination. This in silico analysis aimed to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most widely administered COVID-19 vaccines, which could induce autoimmunity in predisposed individuals. Methods: The FASTA sequence of the protein encoded by the BNT-162b2 vaccine served as the key input to the Immune Epitope Database and Analysis Resource. Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC-ligand assays without MHC restriction were searched and analyzed. HLA disease associations were screened on the HLA-SPREAD platform by selecting only positive markers. Results: By 7 May 2023, a total of 5693 epitopes corresponding to 21 viral but also human proteins were found. The latter included CHL1, ENTPD1, MEAF6, SLC35G2, and ZFHX2. Importantly, some autoepitopes may be presented by HLA alleles positively associated with various immunological diseases. Conclusions: The protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals through a molecular mimicry mechanism. Genotyping for HLA alleles may help identify individuals at risk. However, further wet-lab studies are needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Donor–recipient matching is a highly individualized and complex component of solid organ transplantation. Flowcytometry crossmatching (FC-XM) is an integral step in the matching process that is used to detect pre-formed deleterious anti-donor immunoglobulin. Despite high sensitivity in detecting cell-bound immunoglobulin, FC-XM is not able to determine the source or function of immunoglobulins detected. Monoclonal antibody therapeutic agents used in a clinic can interfere with the interpretation of FC-XM. We combined data from the prospectively maintained Antibody Society database and Human Protein Atlas with a comprehensive literature review of PubMed to summarize known FC-XM-interfering antibody therapeutics and identify potential interferers. We identified eight unique FC-XM-interfering antibody therapeutics. Rituximab (anti-CD20) was the most-cited agent. Daratumuab (anti-CD38) was the newest reported agent. We identified 43 unreported antibody therapeutics that may interfere with FC-XM. As antibody therapeutic agents become more common, identifying and mitigating FC-XM interference will likely become an increased focus for transplant centers. [ABSTRACT FROM AUTHOR]

The risk of Graves' orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were related to both GO and TC and/or LDL levels. Therefore, the aim of the study was to compare the TC/LDL results in patients in whom GO-related HLA alleles were present to those in whom they did not occur. HLA classes were genotyped using a next-generation sequencing method in 118 patients with Graves' disease (GD), including 63 and 55 patients with and without GO, respectively. Lipid profiles were assessed at the time of the GD diagnosis. A significant correlation between the presence of GO high-risk alleles (HLA-B*37:01 and C*03:02) and higher TC/LDL levels was found. Additionally, the presence of alleles associated with non-GO GD (HLA-C*17:01 and B*08:01), as well as alleles in linkage disequilibrium with B*08:01 (i.e., HLA-DRB1*03:01 and DQB1*02:01), was correlated with lower TC levels. These results further confirm the significance of TC/LDL in the risk of GO development and provide evidence that associations between TC/LDL and GO can be HLA-dependent. [ABSTRACT FROM AUTHOR]

In this study, we investigated HLA class I and class II allele and haplotype frequencies in Emiratis and compared them to those of Asian, Mediterranean, and Sub-Saharan African populations. Methods: Two-hundred unrelated Emirati parents of patients selected for bone marrow transplantation were genotyped for HLA class I (A, B, C) and class II (DRB1, DQB1) genes using reverse sequence specific oligonucleotide bead-based multiplexing. HLA haplotypes were assigned with certainty by segregation (pedigree) analysis, and haplotype frequencies were obtained by direct counting. HLA class I and class II frequencies in Emiratis were compared to data from other populations using standard genetic distances (SGD), Neighbor-Joining (NJ) phylogenetic dendrograms, and correspondence analysis. Results: The studied HLA loci were in Hardy–Weinberg Equilibrium. We identified 17 HLA-A, 28 HLA-B, 14 HLA-C, 13 HLA-DRB1, and 5 HLA-DQB1 alleles, of which HLA-A*02 (22.2%), -B*51 (19.5%), -C*07 (20.0%), -DRB1*03 (22.2%), and -DQB1*02 (32.8%) were the most frequent allele lineages. DRB1*03~DQB1*02 (21.2%), DRB1*16~DQB1*05 (17.3%), B*35~C*04 (11.7%), B*08~DRB1*03 (9.7%), A*02~B*51 (7.5%), and A*26~C*07~B*08~DRB1*03~DQB1*02 (4.2%) were the most frequent two- and five-locus HLA haplotypes. Correspondence analysis and dendrograms showed that Emiratis were clustered with the Arabian Peninsula populations (Saudis, Omanis and Kuwaitis), West Mediterranean populations (North Africans, Iberians) and Pakistanis, but were distant from East Mediterranean (Turks, Albanians, Greek), Levantine (Syrians, Palestinians, Lebanese), Iranian, Iraqi Kurdish, and Sub-Saharan populations. Conclusions: Emiratis were closely related to Arabian Peninsula populations, West Mediterranean populations and Pakistanis. However, the contribution of East Mediterranean, Levantine Arab, Iranian, and Sub-Saharan populations to the Emiratis' gene pool appears to be minor. [ABSTRACT FROM AUTHOR]

We aimed to identify HLA-DRB1, -DQA1, and -DQB1 alleles/haplotypes associated with European, African, or Native American genomic ancestry (GA) in admixed Brazilian patients with type 1 diabetes (T1D). This exploratory nationwide study enrolled 1599 participants. GA percentage was inferred using a panel of 46 ancestry informative marker-insertion/deletion. Receiver operating characteristic curve analysis (ROC) was applied to identify HLA class II alleles related to European, African, or Native American GA, and showed significant (p < 0.05) accuracy for identifying HLA risk alleles related to European GA: for DRB1*03:01, the area under the curve was (AUC) 0.533; for DRB1*04:01 AUC = 0.558, for DRB1*04:02 AUC = 0.545. A better accuracy for identifying African GA was observed for the risk allele DRB1*09:01AUC = 0.679 and for the protective alleles DRB1*03:02 AUC = 0.649, DRB1*11:02 AUC = 0.636, and DRB1*15:03 AUC = 0.690. Higher percentage of European GA was observed in patients with risk haplotypes (p < 0.05). African GA percentage was higher in patients with protective haplotypes (p < 0.05). Risk alleles and haplotypes were related to European GA and protective alleles/haplotypes to African GA. Future studies with other ancestry markers are warranted to fill the gap in knowledge regarding the genetic origin of T1D in highly admixed populations such as that found in Brazil. [ABSTRACT FROM AUTHOR]

Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3–6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1–4 mcg × 1–3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5–10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32–1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1–4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month–2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion. [ABSTRACT FROM AUTHOR]

Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases. [ABSTRACT FROM AUTHOR]

The genetic variants of HLAs (human leukocyte antigens) play a crucial role in the virus–host interaction and pathology of COVID-19. The genetic variants of HLAs not only influence T cell immune responses but also B cell immune responses by presenting a variety of peptide fragments of invading pathogens. Peptide cocktail vaccines produced by using various conserved HLA-A2 epitopes provoke substantial specific CD8+ T cell responses in experimental animals. The HLA profiles vary among individuals and trigger different T cell-mediated immune responses in COVID-19 infections. Those with HLA-C*01 and HLA-B*44 are highly susceptible to the disease. However, HLA-A*02:01, HLA-DR*03:01, and HLA-Cw*15:02 alleles show resistance to SARS infection. Understanding the genetic association of HLA with COVID-19 susceptibility and severity is important because it can help in studying the transmission of COVID-19 and its physiopathogenesis. The HLA-C*01 and B*44 allele pathways can be studied to gain insight into disease transmission and physiopathogenesis. Therefore, integrating HLA testing is suggested in the ongoing pandemic, which will help in the rapid identification of highly susceptible populations worldwide and possibly acclimate vaccine development. Therefore, understanding the correlation between HLA and SARS-CoV-2 is critical in opening new insights into COVID-19 therapeutics, based on previous studies conducted. [ABSTRACT FROM AUTHOR]

Leishmaniasis represents a complex of diseases with a broad clinical spectrum and epidemiological diversity, considered a major public health problem. Although there is treatment, there are still no vaccines for cutaneous leishmaniasis. Because Leishmania spp. is an intracellular protozoan with several escape mechanisms, a vaccine must provoke cellular and humoral immune responses. Previously, we identified the Leishmania homolog of receptors for activated C kinase (LACK) and phosphoenolpyruvate carboxykinase (PEPCK) proteins as strong immunogens and candidates for the development of a vaccine strategy. The present work focuses on the in silico prediction and characterization of antigenic epitopes that might interact with mice or human major histocompatibility complex class I. After immunogenicity prediction on the Immune Epitope Database (IEDB) and the Database of MHC Ligands and Peptide Motifs (SYFPEITHI), 26 peptides were selected for interaction assays with infected mouse lymphocytes by flow cytometry and ELISpot. This strategy identified nine antigenic peptides (pL1-H2, pPL3-H2, pL10-HLA, pP13-H2, pP14-H2, pP15-H2, pP16-H2, pP17-H2, pP18-H2, pP26-HLA), which are strong candidates for developing a peptide vaccine against leishmaniasis. [ABSTRACT FROM AUTHOR]

The clinical outcome of Puumala hantavirus (PUUV) infection shows extensive variation, ranging from inapparent subclinical infection (70–80%) to severe hemorrhagic fever with renal syndrome (HFRS), with about 0.1% of cases being fatal. Most hospitalized patients experience acute kidney injury (AKI), histologically known as acute hemorrhagic tubulointerstitial nephritis. Why this variation? There is no evidence that there would be more virulent and less virulent variants infecting humans, although this has not been extensively studied. Individuals with the human leukocyte antigen (HLA) alleles B*08 and DRB1*0301 are likely to have a severe form of the PUUV infection, and those with B*27 are likely to have a benign clinical course. Other genetic factors, related to the tumor necrosis factor (TNF) gene and the C4A component of the complement system, may be involved. Various autoimmune phenomena and Epstein-Barr virus infection are associated with PUUV infection, but hantavirus-neutralizing antibodies are not associated with lower disease severity in PUUV HFRS. Wide individual differences occur in ocular and central nervous system (CNS) manifestations and in the long-term consequences of nephropathia epidemica (NE). Numerous biomarkers have been detected, and some are clinically used to assess and predict the severity of PUUV infection. A new addition is the plasma glucose concentration associated with the severity of both capillary leakage, thrombocytopenia, inflammation, and AKI in PUUV infection. Our question, "Why this variation?" remains largely unanswered. [ABSTRACT FROM AUTHOR]

Measure of drug-mediated immune reactions that are dependent on the patient's genotype determine individual medication protocols. Despite extensive clinical trials prior to the license of a specific drug, certain patient-specific immune reactions cannot be reliably predicted. The need for acknowledgement of the actual proteomic state for selected individuals under drug administration becomes obvious. The well-established association between certain HLA molecules and drugs or their metabolites has been analyzed in recent years, yet the polymorphic nature of HLA makes a broad prediction unfeasible. Dependent on the patient's genotype, carbamazepine (CBZ) hypersensitivities can cause diverse disease symptoms as maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms or the more severe diseases Stevens-Johnson-Syndrome or toxic epidermal necrolysis. Not only the association between HLA-B*15:02 or HLA-A*31:01 but also between HLA-B*57:01 and CBZ administration could be demonstrated. This study aimed to illuminate the mechanism of HLA-B*57:01-mediated CBZ hypersensitivity by full proteome analysis. The main CBZ metabolite EPX introduced drastic proteomic alterations as the induction of inflammatory processes through the upstream kinase ERBB2 and the upregulation of NFκB and JAK/STAT pathway implying a pro-apoptotic, pro-necrotic shift in the cellular response. Anti-inflammatory pathways and associated effector proteins were downregulated. This disequilibrium of pro- and anti-inflammatory processes clearly explain fatal immune reactions following CBZ administration. [ABSTRACT FROM AUTHOR]

Simple Summary: The major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and the beta-2 microglobulin (B2M) genes, play a key role in neoantigens presentation to the immune system. We analyzed allelic imbalance (AI) of the respective chromosomal regions by multiplex PCRs using microsatellite markers in biopsies of 158 patients with gastric/gastroesophageal adenocarcinoma before neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx) for an association with clinical outcome of the patients. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed interesting differences. Of note, AI at markers of the HLA region was associated with a decreased survival only in responding but not in non-responding patients. No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant CTx. We aimed to determine the clinical and prognostic relevance of allelic imbalance (AI) of the major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and beta-2 microglobulin (B2M) genes, in the context of neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx). Biopsies before CTx were studied in 158 patients with adenocarcinoma of the stomach or gastroesophageal junction. The response was histopathologically evaluated. AI was detected by multiplex PCRs analysis of four or five microsatellite markers in HLA and B2M regions, respectively. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed differences. AI at marker D6S265, close to the HLA-A gene, was associated with an obvious increased risk in responding (HR, 3.62; 95% CI, 0.96–13.68, p = 0.058) but not in non-responding patients (HR, 0.92; 95% CI, 0.51–1.65, p = 0.773). Markers D6S273 and D6S2872 showed similar results. The interaction between AI at D6S265 and response to CTx was significant in a multivariable analysis (p = 0.010). No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant platinum/fluoropyrimidine CTx. [ABSTRACT FROM AUTHOR]

Taiwan has the highest incidence rate of oral cancer in the world. Although oral cancer is mostly an environmentally induced cancer, genetic factors also play an important role in its etiology. Genome-wide association studies (GWAS) have identified nine susceptibility regions for oral cancers in populations of European descent. In this study, we performed the first GWAS of oral cancer in Taiwan with 1529 cases and 44,572 controls. We confirmed two previously reported loci on the 6p21.33 (HLA-B) and 6p21.32 (HLA-DQ gene cluster) loci, highlighting the importance of the human leukocyte antigen and, hence, the immunologic mechanisms in oral carcinogenesis. The TERT-CLMPT1L locus on 5p15.33, the 4q23 ADH1B locus, and the LAMC3 locus on 9q34.12 were also consistent in the Taiwanese. We found two new independent loci on 6p21.32, rs401775 in SKIV2L gene and rs9267798 in TNXB gene. We also found two suggestive novel Taiwanese-specific loci near the TPRS1 gene on 8q23.3 and in the TMED3 gene on 15q25.1. This study identified both common and unique oral cancer susceptibility loci in the Taiwanese as compared to populations of European descent and shed significant light on the etiology of oral cancer in Taiwan. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) is an immune-mediated vasculitis that affects large arteries. It has been hypothesized that viruses may trigger inflammation within the vessel walls. Genetic studies on human leukocyte antigens (HLAs) have previously reported HLA-DRB1*04 as a susceptible allele for GCA and HLA-DRB1*15 as a protective allele for GCA. Here, we discuss the clinical presentation, laboratory findings, HLA class I and class II analysis results, and management of patients with extracranial large-vessel (LV) GCA, detected at least six weeks after recovery from COVID-19. This case series encompassed three patients with LV-GCA (two males and a female with an age range of 63–69 years) whose leading clinical presentation included the presence of constitutional symptoms and significantly elevated inflammatory markers. The diagnosis of LV-GCA was confirmed by CT angiography and FDG-PET/CT, revealing inflammation in the large vessels. All were treated with corticosteroids, while two received adjunctive therapy. By analyzing HLA profiles, we found no presence of the susceptible HLA-DRB1*04 allele, while the HLA-DRB1*15 allele was detected in two patients. In conclusion, LV-GCA may be triggered by COVID-19. We highlight the importance of the early identification of LV-GCA following SARS-CoV-2 infection, which may be delayed due to the overlapping clinical features of GCA and COVID-19. The prompt initiation of therapy is necessary in order to avoid severe vascular complications. Future studies will better define the role of specific HLA alleles in patients who developed GCA following COVID-19. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019. Anti-SARS-CoV-2 spike (S) and neutralizing antibodies (Abs) are measured to evaluate the efficacy of vaccines. Human leukocyte antigen (HLA) may be associated with vaccine efficacy. Here, we investigated the association of HLA polymorphisms with the production of anti-SARS-CoV-2 S or neutralizing Abs in vaccinated rheumatoid arthritis (RA) patients in Japan. Genotyping of DRB1 and DQB1 was conducted in 87 Japanese RA patients vaccinated with BNT162b2. Associations of allele or haplotype carrier frequencies with anti-SARS-CoV-2 S or neutralizing Abs were examined. DRB1*12:01 was significantly positively associated with the production of S Ab (p = 0.0225, odds ratio [OR] 6.08, 95% confidence interval [CI] 1.32–28.03). The DQB1*03:01 allele carrier frequency tended to be higher in high responders of S Ab. Allele carrier frequencies of DRB1*15:01 (p = 0.0102, OR 9.26, 95% CI 1.65–52.01) and DQB1*06:02 (p = 0.0373, OR 7.00, 95% CI 1.18–41.36) were higher in responders of neutralizing Ab. Haplotype and two-locus analyses of DRB1 and DQB1 suggested that DRB1 alleles were the primary drivers of these associations. Logistic regression analysis showed associations of these alleles independent of clinical characteristics. Independent associations were found between HLA alleles and anti-SARS-CoV-2 Ab production by vaccinated RA patients. [ABSTRACT FROM AUTHOR]