Search Results (679)

Background/Objectives: Hepatocellular carcinoma (HCC) arises through heterogeneous pathways involving chronic hepatitis B virus infection, hepatitis C virus infection, alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease, fibrosis, cirrhosis, and environmental exposures. Genome-wide association studies (GWASs) have identified host germline loci associated with HCC susceptibility, but interpretation is complicated by aetiology, ancestry, liver disease stage, and the definition of controls. This narrative review examines current GWAS evidence for HCC, with emphasis on aetiology-specific susceptibility, functional interpretation, cross-disorder genetic effects, and clinical translation. Methods: Studies were identified through iterative searches of PubMed/PMC, publisher pages, academic search tools, and citation tracking, supplemented by targeted searches for major HCC-associated loci. Sources were chosen based on relevance to GWAS discovery, replication, meta-analysis, functional interpretation, polygenic risk modelling, or HCC risk stratification, rather than by a formal systematic review protocol. Results: Viral HCC studies most often implicate immune regulation and antigen presentation, including MICA, HLA-DQ, HLA-DQB1, HLA class I, HCP5, STAT4, DEPDC5, and FAM114A1. Alcohol-related, metabolic, and non-viral HCC studies more often implicate hepatic lipid metabolism, telomere biology, iron metabolism, steatosis, and cirrhosis-related pathways, including PNPLA3, TM6SF2, TERT, HSD17B13, APOE, HFE, and MTARC1. Recent studies increasingly combine GWASs with fine-mapping, functional annotation, transcriptomic analyses, and risk modelling. Conclusions: HCC genetic susceptibility is highly aetiology-specific and overlaps with other liver and metabolic disorders, but discoveries from genetic studies have not yet been translated into routine clinical practice. Future work should prioritise multi-ancestry cohorts, disease-stage-aware controls, functional validation, and prospectively tested genetic risk models. Full article

Aspartame is a widely used artificial sweetener, but its possible relationship with rheumatoid arthritis (RA) remains insufficiently understood. This study aimed to explore, rather than prove, potential molecular links between aspartame-related targets and RA-associated gene networks. Three public RA transcriptomic datasets (GSE55235, GSE55457, and GSE77298) from the Gene Expression Omnibus (GEO) database were integrated as discovery/training data. Because these datasets included different tissue origins, batch correction was used to reduce dataset-level technical variation, whereas tissue-origin-related biological variation was not assumed to be fully removable. After differential expression analysis, RA-associated differentially expressed genes (DEGs) were identified. The single-cell dataset GSE200815 was used for cell annotation and cellular expression visualization; because its comparator group consists of psoriatic arthritis (PsA) samples rather than healthy controls, single-cell results were interpreted as RA-vs-PsA observations and were not treated as disease-versus-healthy-control evidence. Potential targets of aspartame were retrieved from ChEMBL, SwissTargetPrediction, and the Similarity Ensemble Approach (SEA), and were intersected with RA-related DEGs to construct an aspartame-gene-RA regulatory network. Diagnostic models were developed using 113 machine-learning algorithm combinations to determine an optimal multigene model and its core genes. HLA-DRB1 was selected for exploratory scTenifoldKnk-based virtual knockout mainly because it was included in the optimal model and has a well-established role in RA immunogenetics; the single-cell analysis was used only to describe cellular distribution in the RA/PsA dataset. Molecular docking was then used to evaluate the possible interaction between aspartame and HLA-DRB1. Forty-four intersected genes linked the predicted aspartame targets with RA DEGs. The random forest plus partial least-squares generalized linear model (RF + plsRglm) identified 16 core genes. Network-level interpretation indicated that these genes were distributed across immune/antigen-processing, inflammatory-signaling, protease/extracellular-matrix-remodeling, adhesion, metabolic, and proliferation-related modules; therefore, HLA-DRB1 was treated as a prioritized immune-module candidate rather than as the sole driver of the network. Following virtual knockout of HLA-DRB1, affected genes were enriched in extracellular matrix organization, extracellular structure organization, extracellular matrix, collagen trimer, extracellular matrix structural constituent, and collagen binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included integrin signaling, focal adhesion, proteoglycans in cancer, cytoskeleton in muscle, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling. Molecular docking showed a minimum binding energy of −6.7 kcal/mol, which was more negative than the preset stability criterion of −5.0 kcal/mol, and the docking pose suggested contacts around ARG-146. This integrative analysis suggests a hypothesis-generating association between aspartame-related predicted targets and RA-relevant molecular networks involving HLA-DRB1 and other core genes. The findings do not establish causality and require experimental, epidemiological, biophysical, and tissue-stratified validation before any causal or clinical inference can be made. Full article

Post-translational modification (PTM) neoantigens have emerged as key drivers of autoimmune inflammation. However, standardized protocols for MHC Class II tetramer preparation for the detection of such antigen-specific T cells remain limited, hindering the broader application of this important discovery. This study systematically engineered an HLA-DR4 (HLA-DRB1*04:02 and HLA-DRA*01:01) tetramer platform based on carboxyethyl-modified neoantigen ITGA2B peptide (ITG-CE), a PTM associated with autoimmune diseases (AUIDs) such as Ankylosing Spondylitis (AS). The platform provides a major histocompatibility complex (MHC) Class II tetramer associated with the PTM neoantigen and integrates modular protein construct, a controllable PTM peptide exchange strategy, and a specific T cell receptor (TCR) validation model. It can be employed to investigate PTM neoantigen presentation and CD4⁺ T cell auto-reactivity, providing extensive application value for future research into the mechanisms of PTM-induced AUIDs and immune monitoring. Full article

Dengue is an arboviral disease of global significance caused by Orthoflavivirus denguei (DENV), which has four antigenically distinct serotypes. The envelope (E) protein plays a critical role in viral entry and eliciting immune responses. This study aimed to compare the biochemical and immunological properties of the E protein across the four DENV serotypes using in silico approaches. E protein reference sequences were retrieved from RefSeq and analyzed with various bioinformatics tools. Sequence alignment revealed identities ranging from 63.08% to 77.69%. Biochemical analysis showed minimal variation in molecular weight and isoelectric point; however, the net charge of DENV-3 E protein was notably lower. Secondary structure predictions indicated a predominance of alpha-helices in DENVs-1/2, while DENVs-3/4 featured more beta-sheets. Post-translational modification analysis revealed mostly casein kinase II phosphorylation sites across all serotypes, with DENV-4 uniquely presenting also tyrosine kinase sites. Amino acids W231/D341 in DENV-1, Q86 in DENVs-2/4, and D87/D339 in DENV-3 showed maximum antigenicity scores in B cell recognition, while the human leukocyte antigen (HLA) alleles B*08:01/B*39:01 and DRB4*01:01, recognized by T cells, presented the highest number of predicted epitopes for the different DENV serotypes. Conservation analysis showed that the major antigenic regions highlighted in this study are highly conserved among contemporary DENV isolates despite the genetic variability observed within each serotype. These findings suggest that subtle structural differences in the E protein may contribute to distinct immunogenic profiles, highlighting candidate regions for future investigation. Full article

Melanoma treatment has been transformed by immune checkpoint blockade, yet many patients still experience primary resistance, limited durability of response, or acquired resistance. These limitations underscore the need for additional targets that reflect melanoma biology while enabling new therapeutic strategies, particularly in biologically defined settings of immune escape such as checkpoint-resistant, HLA-low, dedifferentiated, or stress-adapted melanoma. The B7-H6/NKp30 axis has gained attention as a link between tumor cell stress, immune recognition, and therapy-related adaptation. B7-H6 (NCR3LG1), an inducible ligand for NKp30, has been detected in melanoma cell lines and tumor specimens, and soluble B7-H6 has been identified in a subset of patients. Membrane-bound B7-H6 may support NK-cell activation, whereas ligand shedding and accumulation of soluble B7-H6 may reduce effective antitumor recognition and promote immune evasion. Emerging evidence further suggests that B7-H6 expression may be linked to tumor-intrinsic programs relevant to melanoma cell survival, migration, and adaptation to therapeutic stress. However, B7-H6 is not yet a validated predictive biomarker or an established therapeutic target in melanoma, and current evidence remains limited by small melanoma-specific datasets, incomplete information on spatial and temporal heterogeneity, and the absence of melanoma-focused clinical validation. In this review, we examine the role of the B7-H6/NKp30 axis in immune surveillance, tumor escape, biomarker development, and therapeutic targeting, and discuss its translational potential in melanoma as an emerging but incompletely validated pathway that warrants focused investigation in melanoma states where conventional immune control is limited. Full article

Human leukocyte antigen (HLA) loci are highly polymorphic genome regions, with allele frequencies varying significantly across different populations. Population HLA frequency databases may contain biases and make cross-study comparison complicated due to varying data curation protocols, genotyping methodologies, resolution, and inconsistencies in the selection criteria for population samples. This study presents HLA allele frequencies of class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1, -DQA1), as well as their combined haplotypes obtained from over 18,000 whole genome sequencing samples of the Russian population. The cohort was stratified based on PCA and admixture components, providing frequencies for 14 different ethnic groups. For 12 groups cohort size allowed us to reach average saturation of 96% of allele frequencies in groups. Moreover, we demonstrated the utility of composed statistics for disease population study using type 1 diabetes (T1D) as an example. Genetically defined population clusters with similar aggregated genetic risk for T1D demonstrated substantial differences in frequencies of risk and protective HLA alleles. Obtained frequency data were made publicly available through the Allele Frequency Net Database improving previously sparse coverage in HLA frequencies data for the East Europe and North Asia regions. Full article

Background/Objectives: Patients with acute anterior uveitis (AAU) have a high prevalence of occult spondyloarthropathy (SpA). Only one previous study investigated ultrasonographic (US) changes at peripheral entheses and joints in patients with acute anterior uveitis (AAU) and no study has used these data in recognizing unknown SpA as defined by ASAS criteria. No previous study compared non-granulomatous (NGAU) with granulomatous uveitis (GAU) for these US features. The objective of this study was to investigate the prevalence of US enthesis and joint abnormalities in a consecutive series of GAU and NGAU patients and to use these data in recognizing unknown SpA as defined by ASAS criteria. Methods: A total of 152 consecutive patients diagnosed with AAU [103 NGAU (42 B27−, 61 B27+) and 49 GAU] from the Immunology Eye Unit (AUSL-IRCCS Reggio Emilia, Italy) were enrolled in this study. Six peripheral entheses as well as knee and ankle joints were bilaterally evaluated by US according to standard methods. The presence of any elementary lesion, structural damage and active enthesitis, according to OMERACT definitions, was recorded. ASAS classification criteria of SpA were integrated with the US data of active enthesitis and joint synovitis in defining the presence of enthesitis and arthritis. Results: NGAU patients had a higher prevalence of entheseal erosions (11.9% vs. 9%, P0 0.009), of enthesis exhibiting a PD signal (29.7% vs. 12.2%, p = 0.025) and of active enthesitis (23% vs. 8.2%, p = 0.026) compared with GAU group. Unknown SpA as defined by ASAS criteria was recognized in 29 patients by clinical and MR/Rx examination of sacroiliac joints and in 13 additional patients with the use of US data. Conclusions: Acute entheseal lesions and erosions are associated with NGAU, without apparent influence of HLA-B27 positivity. US examination helps to recognize previously unknown SpA and to define the disease phenotype of patients, moving toward more personalized treatment. Full article

Single-cell RNA sequencing (scRNAseq) captures unique profiles of individual cells and uncovers cell-to-cell communication (CCC) through ligand–receptor (LR) interactions. Moreover, it reveals signalling mechanisms underlying cellular heterogeneity and complexity in downstream responses in healthy and disease states. In this work, we developed a composite computational pipeline to track CCC patterns in the tumour microenvironment (TME) during Multiple Myeloma (MM) progression as a case study. Three publicly available scRNAseq datasets were analysed using basic single-cell analytics and stage-specific CCC networks were reconstructed with CellChat, in a microenvironment-specific approach. Basic network analytics (CytoHubba) were performed to identify key cell nodes based on network topology metrics; differential network rewiring (DyNet) was performed to calculate rewired nodes. Follow-up analyses were conducted with NicheNet to investigate downstream responses and target genes influenced by CCC. Our network analyses highlighted dendritic cells (DCs), plasmacytoid DCs (pDCs), hematopoietic stem cells (HSCs), red pulp macrophages (RPMs), natural killer (NK) cells, and T and B cells as important cell nodes. Moreover, in neutrophils, the HLA-DRA–JUN–FOS was shown to play a key role in the progression of monoclonal gammopathies of uncertain significance (MGUS) to active MM by supporting cancer hallmarks and MM pathophysiology. To conclude, our work suggests an explanatory–computational pipeline that incorporates well-known frameworks in a hypothesis-driven scope, which leads to results relevant to the pathophysiology of MM. Full article

Spondyloarthritis represents a group of chronic immune-mediated rheumatic diseases that manifest as peripheral or axial musculoskeletal involvement. In axial spondyloarthritis (axSpA), the milestones of structural damage are represented by inflammation, followed by erosions in the sacroiliac joints (SIJ) and new bone formation. The purpose of this narrative review is to address the unmet needs regarding targeted risk stratification of disease progression in axSpA. While studies concerning predictive biomarkers have been conducted, their use in clinical practice has not yet been validated. Analysis of disease progression in patients recently diagnosed with non-radiographic axSpA, with fulfillment of the Assessment of Spondyloarthritis International Society criteria, determined a mean time of structural changes progression of 2.4 years. While factors such as human leukocyte antigen (HLA)-B27 and C-reactive protein are useful in classifying patients into risk categories regarding radiographic progression, novel biomarkers are needed in clinical practice to further facilitate treatment strategy selection. Choosing biomarkers to analyze the potential of both spinal and SIJ radiographic progression is useful in monitoring patients and reducing the burden of disease. Fetuin-A, sclerostin, and autoantibodies against Cluster of Differentiation 74 (anti-CD74) were associated with SIJ changes in various studies. Regarding spinal structural damage, adipokines, particularly leptin and visfatin, have been extensively studied and have shown promising results. Dickkopf-1, a regulator of the Wnt signaling pathway, vascular endothelial growth factor, and matrix metalloproteinase-3 have also presented associations with worsening modified Stoke Ankylosing Spondylitis Spine Score. The potential of each biomarker may be heightened by their use in prediction models with the purpose of implementation in clinical practice, particularly in improving patient outcomes and tailoring treatment strategies for individuals with spinal structural damage. Full article

Lyssaviruses are neurotropic viruses that cause fatal encephalitis, with the rabies virus as the most prominent member. The viral glycoprotein (G) plays a key role in infection and is the main target of adaptive immune responses. This study aimed to comparatively analyze linear B- and CD4⁺ T-cell epitopes in the G protein ectodomain of lyssaviruses from phylogroups I (RABV, EBLV-1, EBLV-2, DUVV, and ABLV) and II (LBV and MOKV) using bioinformatics tools. Protein sequences were obtained from GenBank, processed to isolate ectodomains, aligned for identity analysis, and used to generate consensus sequences. CD4⁺ T-cell epitopes were predicted based on HLA-II binding affinity, while linear B-cell epitopes were identified using physicochemical properties and assessed for N-glycan masking. Amino acid identity ranged from 76.71% to 83.79% in phylogroup I and 82.72% in phylogroup II. Phylogroup I showed a higher density of HLA-II epitopes (0.22) than phylogroup II (0.18). Despite differences in antigenicity distribution, conserved linear B-cell epitopes in both phylogroups overlapped with peptides binding to HLA-II DRB1*15:01 and were not masked by N-glycans. These findings highlight putatively conserved antigenic regions identified through computational analysis and may support future studies focused on the development of improved vaccines and immunoprophylactic strategies against lyssaviruses. Full article

Background: Crohn‘s disease (CD) is frequently complicated by extraintestinal manifestations, including axial spondyloarthritis (axSpA). Both diseases share genetic (HLA-B27, IL23R, ERAP1/2) and immunopathological mechanisms (Th17/IL-23 axis). Their co-occurrence increases the risk of systemic complications such as AA amyloidosis. Case presentation: We report a 42-year-old male with HLA-B27-positive axSpA who developed CD shortly after initiating secukinumab (IL-17A inhibitor). Following discontinuation of secukinumab and surgical management of CD, the patient experienced rapidly progressive AA amyloidosis affecting the kidneys and intestines, leading to acute kidney injury and requiring hemodialysis. Potential triggering factors included a preceding intestinal infection and self-administered infrared physiotherapy. Conclusions: Coexistent CD and axSpA significantly increases the risk of severe AA amyloidosis. IL-17 inhibitors should be used with extreme caution in patients with subclinical or active CD. Early screenings for proteinuria and low-threshold biopsy are essential to detect AA amyloidosis. In patients with both conditions, TNF-α or IL-12/23 inhibitors are preferred over IL-17 blockade. Full article

Background/Objectives: Genetic variation in human leukocyte antigen (HLA) genes may contribute to inter-individual differences in infectious-disease susceptibility and clinical outcomes. This study aimed to determine the genotype frequency of HLA Class I and Class II loci in patients with COVID-19 in Saudi Arabia and to examine their associations with survival and clinical severity. Methods: A prospective observational study was conducted at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia, from January 2022 to December 2023. Genomic DNA was extracted, and polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) testing was performed to screen HLA genetic variation. Patients were grouped by survival status (recovered or deceased) and clinical severity: Stage A (asymptomatic), Stage B (mild), Stage C (moderate), and Stage D (severe). Results: In total, 123 patients with COVID-19 were included; 102 (82.9%) recovered and 21 (17.1%) died. ICU admission was more frequent among deceased patients than among recovered patients (95.2% versus 51.0%, p = 0.0001). At the locus level, HLA-DPB1 represented the largest proportion of HLA calls (21%). In call-position-specific allele-group analyses, B*15 in Allele 1 (14.3% versus 1.0%, p = 0.016), C*06 in Allele 2 (42.9% versus 18.6%, p = 0.023), DRB1*10 in Allele 1 (19.0% versus 4.9%, p = 0.045), and DQB1*05 in Allele 1 (33.3% versus 11.8%, p = 0.021) were significantly more frequent among deceased patients, whereas DQB1*03 in Allele 1 was significantly more frequent among recovered patients (45.1% versus 14.3%, p = 0.013). Severity analyses showed call-position-specific differences involving C*15, C*06, B*14, B*39, B*53, and DQB1*03. Vaccination status did not differ significantly by survival status or across the four clinical severity stages. Conclusions: Selected HLA Class I and Class II allele groups may be associated with COVID-19 survival and clinical severity patterns in this Saudi cohort. These findings should be interpreted cautiously given the cohort size and call-position-specific nature of the analyses. Full article

Type 1 diabetes (T1D) is driven by autoreactive CD4⁺ T-cell responses to pancreatic beta cell antigens presented by disease-associated human leucocyte antigen (HLA) class II molecules. However, the molecular mechanisms by which subtle antigenic modifications promote pathogenic immunity remain incompletely defined. Recent immunopeptidomic studies have identified a cysteine-to-serine substitution at position 19 of the insulin B chain, referred to as InsC19S, as a microenvironment-driven neoepitope that can be presented by HLA class II molecules, including HLA-DQ8, and is recognized by diabetogenic CD4⁺ T cells. In this study we explore potential structural and thermodynamic mechanisms that may contribute to the enhanced immunogenicity associated with this single-amino-acid modification. Using molecular dynamics simulations combined with coarse-grained free-energy-perturbation analyses, we compared HLA DQ8 complexes bound to wild-type (WT) insulin and InsC19S peptides. The InsC19S variant is predicted in simulations to exhibit enhanced binding stability, characterized by increased hydrogen bond occupancy, reduced peptide conformational mobility, and a more favorable binding free energy. In addition, the modified peptide is predicted to induce peptide-dependent conformational adjustments within the HLA-DQ8 peptide-binding groove, resulting in expansion of the conformational landscape and stabilization of distinct low-energy states that are not accessed by the WT complex. Principal component analysis and free-energy landscape mapping suggest that this mutation may promote altered collective motions within HLA DQ8 that are consistent with enhanced peptide major histocompatibility complex (MHC) persistence and optimized antigen presentation geometry. Together, these computational observations suggest a structural framework that may help explain the preferential presentation and pathogenic recognition of InsC19S reported in experimental studies. These findings provide a molecular-level framework that may help link microenvironment-driven insulin neoepitope formation to altered peptide–MHC stability and conformational dynamics in HLA-DQ8. Full article

Background and Objectives: Sjögren’s disease (SjD) is a chronic autoimmune disorder in which the immune system attacks the glands that produce tears and saliva, leading to symptoms such as dry eyes and dry mouth. If left untreated, SjD can also cause inflammation and damage to other parts of the body, including the skin, lungs, kidneys, and nervous system, and increase the risk of developing lymphoma. The human leukocyte antigen (HLA) class II molecule HLA-DR3 is strongly associated with SjD. Materials and Methods: To investigate how post-translational modifications (PTMs) influence the presentation of SjD-associated autoantigens by HLA-DR3, we employed a computational framework to determine the binding of PTM-mimic peptides to HLA-DR3. We further supported the in-silico results with in-vitro experiments. Results: Our analysis revealed that PTM-mimic substitutions at canonical anchor positions rarely improved predicted binding affinity using the Stabilized Matrix Method, with most modifications resulting in reduced affinity. However, a comprehensive analysis of full-length SjD-associated autoantigen sequences (Ro60, Ro52, La) identified discrete regions with high densities of PTM-eligible anchor sites, specifically, the Ro60 HEAT solenoid, Ro52 RING/B-box/PRY-SPRY modules, and the La motif-RRM1 region, suggesting that PTMs may alter epitope presentation in a sequence-dependent manner. Experimental validation of selected PTM-mimic peptides showed enhanced T cell responses, which were associated with increased binding affinity to HLA-DR3. Structural modeling of a representative complex revealed that PTM-mimic peptides adopt a slightly shifted backbone orientation and altered side-chain positioning, leading to a larger peptide–DR3 interaction interface. Conclusions: These findings provide new insights into the role of PTMs in shaping the immunogenicity of SjD-associated autoantigens and highlight the potential for PTM-mimic peptides to modulate T cell responses in SjD. Full article

In this study, we combined computational predictions with experimental validation as a hybrid strategy to explore whether the E protein of tick-borne encephalitis virus (TBEV) possesses autoimmune potential. Using in silico homology searches, we identified two viral epitopes (evglekl and vtgtqgt) within the TBEV E protein that share sequence identity with fragments of the human proteins DNAH7 and CSMD2. Antibodies against these epitopes were detected in the plasma of a subset of patients after natural TBEV infection. Notably, no such antibodies were found in recipients of the Tick-E-Vac vaccine, indicating that the current vaccine does not induce cross-reactive humoral responses to these epitopes. Further computational analysis predicted that these epitopes could be presented by HLA class II molecules (alleles DRB1*09:01 and DRB1*07:01), which are known to be associated with autoimmune pathologies. Molecular dynamics simulations confirmed stable binding of the peptides within the HLA grooves, with favorable binding energies. These findings suggest a possible involvement of T-helper cells in the autoreactive process. Natural TBEV infection can give rise to antibodies against epitopes homologous to human proteins, particularly in genetically predisposed hosts. While such homology alone does not predict the onset of autoimmune disease, it represents a risk factor. Full article