Search Results (131)

Suicidality is a complex multifactorial phenomenon strongly associated with major depression and other psychiatric disorders. Building on evidence implicating the Major Histocompatibility Complex (MHC) in modulating the immune and inflammatory processes characterizing psychiatric disorders, we hypothesized that specific HLA-DQB1 and HLA-DRB1 variants may contribute to an increased genetic susceptibility to suicidal behavior. Human Leucocyte Antigen (HLA) typing by sequence-specific primers (PCR-SSP) was performed on a sample of 196 individuals, including 70 non-lethal suicide attempters, 28 cases of completed suicide, and matched controls. The *HLA-DQB1 02/06 (RR 1.60, CI95% 1.22–2.09, p = 0.03 *) and *HLA-DRB1 11/15 (RR 1.70, CI95% 1.3–2.24, p = 0.04 *) genotypes and the HLA-DRB115~DQB103 haplotype (RR 1.58, CI95% 1.22–2.04, p = 0.03 *) were found to favor suicidal behavior. Psychosocial determinants associated with an increased suicidal risk were bereavement of close relatives (linked with HLA-DQB1*02), memory dysfunction (HLA-DQB1*06), disillusionment (HLA-DRB1*07 and HLA-DRB1*15), and self-harm (HLA-DRB1*15). Our findings support the contributory role of HLA polymorphisms in shaping susceptibility to suicidal behavior. Full article

Type 1 Diabetes Mellitus (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells, predominantly manifesting in childhood or adolescence. The lack of clearly interpretable biological markers in the early stages, combined with the insidious onset of the disease, poses significant challenges to early diagnosis and the implementation of preventive strategies. The applicability of classic T1D biomarkers for understanding the mechanisms of the autoimmune process, preclinical diagnostics and treatment efficiency is limited. Despite advances in next-generation sequencing (NGS) technologies, which have enabled large-scale genome-wide association studies (GWASs) and the identification of polygenic risk scores (PRSs) associated with T1D predisposition, as well as progress in bioinformatics approaches for assessing dysregulated gene expression, no universally accepted risk assessment model or definitive predictive biomarker has been established. Until now, the use of new promising biomarkers for T1D diagnostics is limited by insufficient evidence base. However, they have great potential for the development of diagnostic methods on their basis, which has been shown in single or serial large-scale studies. This critical review covers both well-known biomarkers widely used in clinical practice, such as HLA-haplotype, non-HLA SNPs, islet antigen autoantibodies, C-peptide, and the promising ones, such as cytokines, cfDNA, microRNA, T1D-specific immune cells, islet-TCR, and T1D-specific vibrational bands. Additionally, we highlight new approaches that have been gaining popularity and have already demonstrated their potential: GWAS, single-cell transcriptomics, identification of antigen-specific T cells using scRNA-seq, and FTIR spectroscopy. Although some of the biomarkers, in our opinion, are still limited to a research context or are far from being implemented in clinical diagnostics of T1D, they have the greatest potential of being applied in clinical practice. When integrated with the monitoring of the classical autoimmune diabetes markers, they would increase the sensitivity and specificity during diagnostics of early and preclinical stages of the disease. This critical review aims to evaluate the current landscape of classical and emerging biomarkers in autoimmune diabetes, with a focus on those enabling early detection—prior to extensive destruction of pancreatic islets. Another goal of the review is to focus the attention of the scientific community on the gaps in early T1D diagnostics, and to help in the selection of markers, targets, and methods for scientific studies on creating novel diagnostic panels. Full article

Coeliac disease (CD) is a chronic immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals carrying HLA-DQ2 or HLA-DQ8 haplotypes, characterized by small intestinal mucosal damage and systemic manifestations. This systematic review and meta-analysis aimed to compare the effectiveness of urine versus stool GIPS testing for monitoring gluten intake in coeliac patients, providing evidence-based recommendations for clinical practice. A comprehensive literature search was conducted in databases like PubMed and Embase. Studies evaluating urine or stool GIPS testing in coeliac patients were included, focusing on sensitivity, specificity, and patient adherence. The meta-analysis included six studies with a total of 572 participants. The stool GIPS testing demonstrated a pooled sensitivity of 85.1% (95% CI: 79.0–89.9%) and a specificity of 92.5% (95% CI: 88.3–95.6%), making it highly reliable for detecting gluten exposure and ruling out false positives. It also achieved an AUC of 0.9853, indicating excellent diagnostic performance. In contrast, the urine GIPS testing showed a pooled sensitivity of 55.4% (95% CI: 49.6–61.2%) and a specificity of 73.0% (95% CI: 67.4–78.1%), with an AUC of 0.7898. The heterogeneity across the studies was significant (I² > 80%), driven by variations in the population characteristics, sample handling, and testing protocols. These findings emphasize the need for standardized methodologies to enhance the reliability and comparability of results. Full article

With primary membranous nephropathy (pMN), the genetic background is not precisely known. Certain HLA-DQ serotypes however like HLA-DQ 2.5, and single-nucleotide polymorphisms (SNPs) in the phospholipase A2 receptor 1 (PLA2R1) gene pose a risk for the development of pMN. As antigen presentation is linked to a 3-dimensional conformation of the HLA-DQA/DQB dimer, we thought that the specific HLA-DQ haplotype combinations might also be risk factors in the evolution of MN. The HLA-DQ haplotype combinations and the PLA2R1 gene risk variant (rs4664308) genotypes were examined in 67 patients with MN (52 primary, 15 secondary [sMN]) and 77 controls. Based on the presence or absence of PLA2R1 risk alleles, we used a scoring system to assess the risk and to identify protective HLA-DQ haplotype combinations. The HLA-DQ 2.5 serotype was significantly enriched in both pMN and sMN patients compared to the controls. The pMN group had a significantly higher frequency of the PLA2R1 risk allele compared to the sMN group and the controls. HLA-DQ 2.5 appeared to carry the highest risk for the development of pMN, while HLA-DQ 7.5 and 6.2 seemed to be protective. Our results indicate that the HLA-DQ 2.5 probably carries the highest risk in both pMN and sMN, suggesting that this serotype has less specificity for antigens, and it induces an autoimmune response. Here, PLA2R1 played a role in the development of pMN but not in sMN. Full article

Authorized SARS-CoV-2 vaccines elicit both antibody and T-cell responses; however, benchmark correlates and update decisions have largely emphasized neutralizing antibodies. Motivated by the complementary role of cellular immunity, we designed a prototype polyepitope DNA vaccine encoding conserved human and mouse T-cell epitopes from non-structural proteins of the original strain SARS-CoV-2 lineage. Epitope selection was guided by in silico predictions for common HLA class I alleles in the Brazilian population and the mouse H-2Kb haplotype. To enhance immunogenicity, the polyepitope sequences were fused to glycoprotein D (gD) from Herpes Simplex Virus 1 (HSV-1), an immune activator of dendritic cells (DCs), leading to enhanced activation of antigen-specific T-cell responses. Mice were immunized with two doses of the electroporated DNA vaccine encoding the gD-fused polyepitope, which induced robust interferon-gamma– and tumor necrosis factor-alpha–producing T cell responses compared to control mice. In addition, K18-hACE2 transgenic mice showed protection against intranasal challenge with the original SARS-CoV-2 strain, with reduced clinical symptoms, less weight loss, and decreased viral burden in both lung and brain tissues. The results experimentally confirm the protective role of T cells in vaccine-induced protection against SARS-CoV-2 and open perspectives for the development of universal anti-coronavirus vaccines. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Cetuximab improves survival by combining EGFR inhibition with immune activation. This study evaluated the influence of killer cell immunoglobulin-like receptor (KIR)-mediated immune responses on cetuximab efficacy in 124 metastatic CRC patients: 55 with wild-type (WT) KRAS and 69 with KRAS mutations. Peripheral blood was genotyped for 19 KIR genes and relevant HLA alleles, focusing on key KIR–HLA interactions (2DL1–C2, 3DL1–Bw4, 3DS1–Bw4). KRAS-WT patients showed better outcomes, receiving more treatment cycles (median: 17 vs. 4) and showing slower disease progression (60% vs. 92.8% at 12 months). WT patients had higher frequencies of inhibitory KIRs and the Bw4 allele, with KIR3DS1–Bw4 heterozygosity linked to longer survival (p = 0.013). In KRAS-mutant patients, heterozygous KIR genotypes (AB) and mixed A/B semi-haplotypes were associated with improved survival (p = 0.002). Multivariate analysis confirmed KIR3DS1–Bw4 as a favorable factor in WT patients and AB genotypes as beneficial in KRAS-mutants. In conclusion, KIR–HLA interactions significantly impact cetuximab efficacy in metastatic CRC, with distinct immunogenetic profiles in WT and KRAS-mutant patients. These results highlight the potential of KIR–HLA profiling to guide personalized treatment strategies. Full article

This paper conducts a literature review on the role of natural killer cells in haploidentical hematopoietic stem cell transplantation. Theoretical concepts related to KIR genes are introduced regarding their structure, nomenclature, genetic organization, polymorphism, and inheritance pattern, types of KIR proteins and receptors, HLA ligands for KIR receptors, and the definition of different NK alloreactivity prediction models for the donor of haploidentical hematopoietic stem cell transplantation and the recipient. These models include the following and consider incompatibility: ligand–ligand, receptor–ligand, gene–gene, and KIR haplotype models or the KIR-B donor group. These models consider the presence or absence of specific ligands or receptors and/or KIR genes in the donor and recipient to predict alloreactivity. Determining the best model for predicting KIR alloreactivity and its significance in donor selection algorithms for haploidentical transplantation is still under investigation. Full article

Human Leukocyte Antigen (HLA) genes are remarkable for their structural complexity and polymorphism. Located on chromosome 6 within the Major Histocompatibility Complex (MHC), these genes exhibit significant frequency variations across human populations and play a crucial role in immune responses, disease susceptibility, and transplant compatibility. This study aimed to assess the genetic profiles and HLA-A/HLA-B/HLA-C/HLA-DRB1 haplotype frequencies in a Romanian cohort. Whole venous blood samples were collected from 405 healthy, unrelated Romanian volunteers. Using next-generation sequencing (NGS), the study population was genotyped for HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1) loci. Haplotype frequencies were estimated using the expectation-maximization algorithm, addressing phase and allelic ambiguity. The Romanian cohort was compared with multiple populations sourced from the Allele Frequencies Net Database. The study identified 635 different HLA-A/HLA-B/HLA-C/HLA-DRB1 haplotypes. Among them, two haplotypes had frequencies close to 3%: HLA-A*01:01:01/HLA-B*08:01:01/HLA-C*07:01:01/HLA-DRB1*03:01:01, with a frequency of 3.33%, and HLA-A*02:01:01/HLA-B*18:01:01/HLA-C*17:01:01/HLA-DRB1*11:04:01, with a frequency of 2.84%. All other 633 haplotypes (approximately 99.7% of the total) had frequencies below 1%. The results of the current study underscore the extremely high diversity of HLA haplotypes in this population and the fact that even the most frequent haplotypes are relatively low in prevalence (each under 5% in this cohort). These findings and the great haplotypical diversity detected highlight the importance of NGS and high-resolution HLA typing in hematopoietic stem cell and solid organ transplantation, while also contributing to the better understanding of the area-specific population genetics resulting from historical regional dynamics. Further research with larger cohorts is necessary to validate these findings and expand upon their clinical implications. Full article

Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq on ferroptosis-related genes in distinctive MS phenotypes, we selected putative regulatory variants in the top three DEGs (CDKN1A, MAP1B and EGLN2) and investigated their association with gene expression, plasma/serum parameters and disease severity (EDSS, MSSS, gARMSS). The study included 604 patients with relapsing–remitting (RR) and 241 with progressive (P) MS. The variants CDKN1A rs3176326 and rs3176336, EGLN2 rs111833532, MAP1B rs62363242 and rs1217817 with the previously reported DYSF-ZNF638 locus rs10191329, and MTSS1 rs9643199 were genotyped using TaqMan^®, and the HLA-DRB1*15:01 status was also determined. Significant association of the rare MAP1B rs62363242 allele with PMS in females, independent of HLA-DRB1*1501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. CDKN1A haplotypes were significantly associated with CDKN1A mRNA levels in RRMS and SPMS patients. RAB4B-EGLN2 locus rs111833532 and DYSF-ZNF638 locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of CDKN1A, a part of the p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor and critical regulator of the response to hypoxia, variant rs111833532, along with DYSF-ZNF638 locus rs10191329, was associated with clinical severity. The indicated, novel, sex-specific association of MAP1B rs62363242 with the course of MS remains to be validated in larger studies. Full article

Background/Objectives: Chronic pancreatitis (CP) is a progressive inflammatory condition of the pancreas that leads to irreversible changes in pancreatic structure. The pancreatic α and β cells secrete hormones such as insulin and glucagon into the bloodstream. The pancreatic acinar cells secrete digestive enzymes that break down macromolecules. When these digestive enzymes do not function properly, maldigestion, malabsorption, and malnutrition may result. Presented here is a case study of an individual newly diagnosed with chronic pancreatitis, along with a genetic analysis of his son and an in-silico analysis of two of the variant proteins. Methods: This study was conducted using human subjects, namely, the proband (father) and his son. Medical genetic testing of the proband (father) identified the presence of two variants in the cystic fibrosis transmembrane receptor gene (CFTR): variant rs213950, resulting in a single amino acid change (p. Val470Met), and variant rs74767530, a nonsense variant (Arg1162Ter) with known pathogenicity for cystic fibrosis. Medical testing also revealed an additional missense variant, rs515726209 (Ala73Thr), in the CTRC gene. Cheek cell DNA was collected from both the proband and his son to determine the inheritance pattern and identify any additional variants. A variant in the human leukocyte antigen (rs7454108), which results in the HLA-DQ8 haplotype, was examined in both the proband and his son due to its known association with autoimmune disease, a condition also linked to chronic pancreatitis. In silico tools were subsequently used to examine the impact of the identified variants on protein function. Results: Heterozygosity for all variants originally identified through medical genetic testing was confirmed in the proband and was absent in the son. Both the proband and his son were found to have the DRB1*0301 (common) haplotype for the HLA locus. However, the proband was also found to carry a linked noncoding variant, rs2647088, which was absent in the son. In silico analysis of variant rs213950 (Val470Met) in CFTR and rs515726209 (Ala73Thr) in CTRC revealed distinct changes in predicted ligand binding for both proteins, which may affect protein function and contribute to the development of CP. Conclusions: This case study of a proband and his son provides additional evidence for a polygenic inheritance pattern in CP. The results also highlight new information on the role of the variants on protein function, suggesting additional testing of ligand binding for these variants should be done to confirm the functional impairments. Full article

Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings; however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim that neurotoxin-associated proteins (NAPs) shield BoNT-A from immune detection or are themselves immunogenic, there is limited molecular evidence supporting either view. This study applies computational immunogenetics to explore BoNT-A immunogenicity, focusing on HLA binding and the influence of accessory proteins. Epitope mapping, molecular docking, and HLA binding predictions were used to evaluate interactions between BoNT-A epitopes and selected class II HLA alleles (HLA-DQA1*01:02, HLA-DQA1*03:03, HLA-DQB1*06:04, HLA-DQB1*03:01, and HLA-DRB1*15:01). To assess the potential immunomodulatory role of NAPs, molecular dynamics (MD) simulations, solvent-accessible surface area (SASA) analysis, and electrostatic potential mapping were also conducted. Key epitopes—L11, N25, and C10—showed strong binding affinities to HLA-DQA1*01:02, HLA-DQB1*06:04, and HLA-DQA1*03:03, indicating a potential immunodominant role. NAPs did not obstruct these epitopes but slightly increased their exposure and appeared to stabilize the toxin structure. Electrostatic mapping and binding free energy calculations suggested no significant immunogenic shift in the presence of NAPs. BoNT-A immunogenicity appears to be influenced by HLA allele variability, reinforcing the value of patient-specific genetic profiling. The presumed immunogenic role of NAPs remains unsubstantiated at the molecular level, underscoring the need for evidence-based evaluation over commercial rhetoric. While these findings provide valuable molecular insight, it is important to acknowledge that they are derived entirely from in silico analyses. As such, experimental validation remains essential to confirm the immunological relevance of these predicted interactions. Nonetheless, this computational framework offers a rational basis for guiding future clinical research and the development of HLA-informed BoNT-A therapies. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies. Full article

Background: The human leukocyte antigen (HLA) system represents the most polymorphic segment within human DNA sequences and constitutes a core component of immune defense responses and in understanding population genetics. This research investigates the distribution of HLA class I and II polymorphisms across different ethnic groups in Kazakhstan, offering valuable insights into the genetic diversity and demographic evolution within this region. Methods: We performed an in-depth examination of HLA class I and II polymorphisms across diverse ethnic communities living in Kazakhstan, including Kazakhs, Russians, Uzbeks, Ukrainians, Germans, Tatars, and Koreans. Utilizing data from high-resolution HLA typing studies allowed us to assess allele frequencies alongside haplotype distributions while analyzing genetic interrelations between these populations. Additionally, we performed comparative assessments with global HLA databases to determine the genetic affiliations between these groups and their relationships with neighboring and more distant populations. Results: Our study revealed over 200 HLA alleles within the analyzed populations, and significant variations were observed in their allele and haplotype frequencies. Notably, the Kazakh group exhibited strong genetic ties to Asian and Siberian demographics; conversely, other ethnicities showed associations reflective of their historical roots. Notable alleles included HLA-A*02:01, B*07:02, C*07:02, DRB1*07:01, and DQB1*03:01, commonly observed across various groups. Linkage disequilibrium analysis revealed the presence of population-specific haplotypes, highlighting distinct genetic structures within these communities. Conclusions: The findings highlight the significant genetic diversity in Kazakhstan, influenced by its geographical location at the crossroads of Europe and Asia. These results are pertinent to immunogenetics, transplantation medicine, and personalized healthcare within Kazakhstan and adjacent regions. Future research should expand the sample size and explore disease associations to enhance our comprehension of HLA genetics across Central Asia. Full article

Background/Objectives: The Human Leukocyte Antigen (HLA) system is composed of a set of genes that codify glycoproteins presenting antigenic proteins to clonotypic T cell receptors in order to start the immune response. Class I and Class II classical loci exhibit high allelic diversity; some of them (or their specific combinations that form haplotypes) are quasi-specific or highly frequent in certain populations and thus are useful for population genetic studies. In this study, an HLA genetic comparison of Chimila, Wayúu, Wiwa, and Barranquilla Colombian nonrelated healthy individuals was carried out together with other populations from all over the world to trace their genetic origin, obtain a virtual transplantation list, and inform future epidemiology studies. Methods: HLA-A, -B, -DRB1, and -DQB1 alleles were sequenced using the PCR-SSOP–Luminex method to analyze the HLA genetic profile of each individual. The data obtained were subsequently processed with standard software to obtain HLA alleles, haplotype frequencies, and genetic distances compared with data from global populations to generate relatedness dendrograms and carry out a correspondence analysis. Results: The results obtained place the Chimila, Wayúu, and Wiwa populations phylogenetically close to the other North and South Amerindian populations included in this study. Amerindians are genetically separated from the rest of the world’s populations. Chimila, Wayúu, and Wiwa present unique extended HLA haplotypes and specific alleles, such as HLA-B*48 or HLA-A*24:01, shared with Oceanian populations. Conclusions: These genetic results and anthropological data support prehistorical trans-Pacific (bidirectional) contacts that contributed to the settlement of America and also suggest that the effects of ancient European gene flow cannot be discarded. Full article

Immunotherapies aimed at preserving residual beta cell function in type 1 diabetes have been successful, although the effect has been limited, or raised safety concerns. Transient effects often observed may necessitate redosing to prolong the effect, although this is not always feasible or safe. Treatment with intralymphatic GAD-alum has been shown to be tolerable and safe in persons with type 1 diabetes and has shown significant efficacy to preserve C-peptide with associated clinical benefit in individuals with the human leukocyte antigen DR3DQ2 haplotype. To further explore the feasibility and advantages of redosing with intralymphatic GAD-alum, six participants who had previously received active treatment with intralymphatic GAD-alum and carried HLA DR3-DQ2 received one additional intralymphatic dose of 4 μg GAD-alum in the pilot trial DIAGNODE-B. The participants also received 2000 U/day vitamin D (Calciferol) supplementation for two months, starting one month prior to the GAD-alum injection. During the 12-month follow-up, residual beta cell function was estimated with Mixed-Meal Tolerance Tests, and clinical and immune responses were observed. C-peptide decreased minimally, and most patients showed stable HbA1c and IDAA1c. The mean % TIR increased while the mean daily insulin dose decreased at month 12 compared to the baseline. Redosing with GAD-alum seems to be safe and tolerable, and may prolong the disease modification elicited by the original GAD-alum treatment. Full article