Search Results (546)

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the immune system attacking the central nervous system, leading to demyelination and neurodegeneration. This work investigates the relationship between specific human leukocyte antigen (HLA) polymorphisms and MS, aiming to reveal the immunogenetic background of this disease for more individualized management approaches. This study employed a case–control design, analyzing HLA allele frequencies in 179 MS patients and 200 control subjects using next-generation sequencing, The key findings indicate significant associations between several HLA Class I and II alleles and MS, including HLA-B*35:03:01:03, HLA-C*04:01:01:14, HLA-DRB1*15:01:01:26, and HLA-DQA1*05:05:01:02. These findings emphasize the critical role of HLA molecules in MS Romanian patients. Full article

Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-β signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy. Full article

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Stage IV colorectal cancer has a poor prognosis, and liver metastases are prone to recurrence, even after resection. This study aimed to identify common cancer antigens, using immunohistochemical staining, as promising targets for antigen-specific immunotherapies in colorectal cancer. We analyzed expression levels and intracellular localization of seven common cancer antigens, CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC, and human leukocyte antigen (HLA) class I via immunohistochemical staining of 85 surgical specimens from primaries and liver metastases. Staining intensity and positive staining were scored to evaluate antigen expression. In 25 primaries, seven cancer antigens were expressed in 88–96% of cases, while HLA class I was expressed on the cell membrane in 80.0% of cases. In 60 liver metastases, FOXM1 and SPARC expression were approximately half that observed in the primaries. Other antigens and HLA class I were highly expressed in both. Most of the primaries and liver metastases may benefit from chimeric antigen receptor-T cell therapy targeting CLDN1, EphB4, and LAT1. Cases with high HLA class I expression may be suitable for vaccine-based and T cell receptor-T cell therapy targeting CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC for primaries and targeting antigens, excluding FOXM1 and SPARC, for liver metastases. Full article

The emergence of anti-TNF agents has revolutionized the management of inflammatory bowel disease, yet a significant proportion of patients experience primary non-response or secondary loss of response due to immunogenicity. As the field of precision medicine advances, genetic predictors such as human leukocyte antigen (HLA) variants are gaining increasing attention. This review provides a comprehensive synthesis of current evidence on the role of HLA genotypes in inflammatory bowel disease susceptibility and disease behavior, with a focus on their mechanistic and clinical relevance in anti-TNF therapy. Special emphasis is placed on HLA-DQA1*05, a validated predictor of anti-drug antibody formation and reduced therapeutic durability. We explore the immunological basis of HLA-mediated immunogenicity, summarize pharmacogenetic and biomarker findings, and discuss how HLA typing may be integrated into treatment algorithms to improve patient stratification and long-term outcomes. As immunogenetics continues to inform clinical decision-making, understanding the interplay between HLA polymorphisms and therapeutic response offers new opportunities for biomarker-guided, personalized care in inflammatory bowel disease. Full article

Background: Pancreas and pancreas–kidney transplantation are well-established therapeutic options for patients with type 1 diabetes mellitus (T1DM) and end-stage kidney disease (ESKD), offering the potential to restore endogenous insulin production and kidney function. It improves metabolic control, quality of life, and long-term survival. While surgical techniques and immunosuppressive strategies have advanced considerably, graft rejection and limited long-term graft survival remain significant clinical challenges. Method: To better understand these risks, the genetic and immunological factors that influence transplant outcomes are examined. Beyond traditional human leukocyte antigen (HLA) matching, non-HLA genetic variants such as gene deletions and single-nucleotide polymorphisms (SNPs) have emerged as contributors to alloimmune activation and graft failure. Result: Polymorphisms in cytokine genes, minor histocompatibility antigens, and immune-regulatory pathways have been implicated in transplant outcomes. However, the integration of such genomic data into clinical practice remains limited due to underexplored gene targets, variability in study results, and the lack of large, diverse, and well-characterized patient cohorts. Initiatives like the International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) are addressing these limitations by aggregating genome-wide data from thousands of transplant donors and recipients across multiple centers. These large-scale collaborative efforts aim to identify clinically actionable genetic markers and support the development of personalized immunosuppressive strategies. Conclusions: Overall, genetic testing and genomics hold great promise in advancing precision medicine in pancreas and pancreas–kidney transplantation. Full article

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option. Full article

High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of tumor foci. In this study, we performed single-cell transcriptomic analysis to explore the TME in samples obtained from various sites of tumor foci, with or without the history of Neoadjuvant chemotherapy (NACT). We discovered that chemotherapy reshaped the tumor immune microenvironment, evident through the reduction in human leukocyte antigen (HLA) diversity and the increase in PDCD1/CD274 in CD8_ANXA1, LAMP3+ dendritic cell (DC_LAMP3), and EREG+ monocytes (mono_EREG). Moreover, cancer.cell.2, cancer-associated C3+ fibroblasts (CAF_C3), and Fibrocyte_CD34, which are prone to accumulate in the metastatic site and post-NACT group, harbored poor clinical outcome, reflected in the immune exclusion and tumor progression signaling. Cell–cell communication identified a stronger interaction between cancer.cell.2 and CAF_C3, as well as Fibrocyte_CD34, in post-NACT samples, indicating that chemotherapy reshapes pre-existing cell clusters in a site-dependent manner. Our findings suggest that chemotherapy and sites of foci were critical for the transcriptional reprogramming of pre-existed cell clusters. Our study offers a single-cell phenotype data substrate from which to develop a personalized combination of chemotherapy and immunotherapy. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with limited responsiveness to immune checkpoint inhibitors (ICIs). Cancer vaccine therapy is a promising novel immunotherapeutic approach that stimulates tumor-specific T cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is overexpressed in malignant tumors but minimally expressed in normal tissues, presents a promising target for immunotherapy. This study aimed to evaluate ROR1 as a target for helper T lymphocyte (HTL)-based peptide vaccine immunotherapy in HNSCC. Methods: ROR1 expression in HNSCC tissues was assessed by immunohistochemistry. A novel ROR1-derived epitope (ROR1_403–417) was identified and used to generate ROR1-reactive HTLs. Functional assays measuring IFN-γ and granzyme B secretion, as well as direct cytotoxicity, were performed. The effects of ICIs on HTL activity were also examined. The presence of ROR1-reactive T cells in the peripheral blood of patients with HNSCC was evaluated. Results: ROR1 positivity rates in HNSCC tissues were significantly higher (80.0%) than those in healthy controls (16.7%), and high ROR1 expression correlated with advanced clinical stages. HTL lines recognized the ROR1_403–417 peptide in a human leukocyte antigen (HLA)-DR-restricted manner, secreted effector cytokines, and exhibited direct cytotoxicity against ROR1+ tumor cells. Dual PD-L1/PD-L2 blockade further enhanced HTL responses. ROR1-reactive T cells were detected in the peripheral blood of patients with HNSCC. Conclusions: ROR1 represents a promising target for immunotherapy in HNSCC. The ROR1_403–417 peptide can elicit ROR1-reactive HTLs that exhibit antitumor responses against HNSCC cell lines, which can be enhanced by ICIs. These findings support the potential of ROR1-targeted peptide vaccine therapy for HNSCC. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes. Full article

Background and Objectives: This study explores the immunogenetic associations of human leukocyte antigens (HLAs) and cytokine levels in people living with HIV/AIDS (PLWH) who exhibit HIV-related skin disorders. HIV-related skin disorders, including inflammatory eruptions, atopic and seborrheic dermatitis, psoriasis, and pruritic papular eruption, are common among PLWH. These conditions may be influenced by genetic and immunological factors. This study aims to investigate the associations between HLA class II alleles, cytokine levels, and the presence of HIV-related dermatoses, providing insights into genetic susceptibility and immune mechanisms. Materials and Methods: This study included 115 PLWH with HIV-related skin disorders and a control group of 80 healthy individuals. HLA allele frequencies were analyzed, and cytokine levels (IL-1β, IL-10, IFN-y) were measured in blood samples. Statistical analyses were performed to identify significant differences in allele frequencies and cytokine responses between the groups. Results: Risk alleles (DQB1*0201:0301, OR = 19.4 and DQA1*0101:0501, OR = 4.2) and protective alleles (DRB1*07:13, OR = 0.19, DRB1*01:13, OR = 0.09, DRB1*04:11, OR = 0.07, and DQA1*0501:0501, OR = 0.24) showed statistically significant differences in frequency (p < 0.05) between PLWH and healthy controls. The protective DQA1*0501:0501 allele was associated with elevated levels of IL-1β (p < 0.001, r = 0.79) and IL-10 (p = 0.010, r = 0.63). Increased IL-1β levels may enhance immune responses, while higher IL-10 levels may exert anti-inflammatory effects, potentially reducing susceptibility to HIV-related dermatoses. Regression analysis revealed that IL-1β (Exp(B) = 0.76, p < 0.001) and IFN-γ (Exp(B) = 1.06, p = 0.043) are significant predictors for the likelihood of developing HIV-related dermatoses. An increase in IL-1β levels reduced this likelihood by 24%, while an increase in IFN-γ levels increased it by 6%. Conclusions: The findings emphasize the interaction between HLA class II alleles and cytokine profiles in determining genetic risk and clinical outcomes in PLWH with HIV-related skin disorders. Protective alleles, such as DQA1*0501:0501, may contribute to immune regulation, offering potential targets for therapeutic interventions in PLWH with dermatoses. Our results highlight the importance of IL-1β and IFN-γ as key modulators in the progression of HIV infection and the development of HIV-related dermatoses. Further research is needed to explore the mechanisms underlying these associations, particularly in the Latvian population, to inform targeted therapeutic strategies. Full article

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that leads to inflammation and demyelination, manifesting in either a relapsing–remitting or progressive form. As a multifactorial disease, MS involves both genetic and environmental factors, with a known significant contribution from human leukocyte antigen (HLA) genes, mainly represented by the HLA-DRB1 and HLA-DQB1 loci, which have been linked to either susceptibility or protection, but variably across populations and ethnic groups. We aimed to study the distribution and polymorphism of HLA-DRB1 and HLA-DQB1 alleles in a population with MS from the southern Moroccan region, in comparison with healthy controls. Materials and Methods: A cross-sectional study was conducted over a period of 2 years (2022–2024) in a MS cohort including 40 patients and 100 healthy controls. DRB1 and DQB1 HLA genotyping was performed using a high-resolution reverse sequence-specific oligonucleotide (SSO) method, based on the Luminex system (xMAP technology, One lambda^®). Data were analyzed using SPSS 26; differences in allele frequencies were evaluated by the Chi-square test and Fisher’s exact test. OR (95% CI) was calculated, and FDR corrections were applied for multiple testing. Results: Among the various HLA-DRB1 and DQB1 alleles studied, including those considered as predisposing to MS, the DQB1*02:01 and DRB1*15:01 alleles were more prevalent in MS patients, with 40% and 8.8% vs. 16% and 4.08% in controls respectively, although these differences were not statistically significant (p = 0.06 and p = 0.12). Likewise, the DRB1*15:01-DQB1*06:02 association was significantly more prevalent in the MS group (9%, p = 0.004). In contrast, the DRB1*07:01 allele, linked to protection against MS in many populations, was significantly predominant in controls (17%, p = 0.004). Similarly, the DRB1*07:01–DQB*02:01 combination was rather more frequent in controls (12%, p = 0.01). Confronted to MS clinical forms, we remarkably noted that the DRB1*13:03 allele was found only among relapsing–remitting MS (RRMS) patients (6%, p = 0.003), while DQB1*02:01 was significantly associated with RRMS (42.1%) and primary progressive MS (41%, p = 0.001), with an intermediate Expanded Disability Status Scale (EDSS) score, which may indicate a possible link with disease progression and severity. Conclusions: The results of our study highlighted particular HLA alleles, DRB1 and DQB1, alone or in combination, as potential immunogenic factors of susceptibility to MS in a population from southern Morocco, while other alleles seem rather to protect against the disease. This HLA polymorphism is also reflected in the clinical forms of the disease, showing a tendency toward severity for certain alleles. However, such preliminary results need to be consolidated and confirmed by studies carried out on a larger population sample, and compared with others on a national scale. Full article

The extensive research and studies conducted over the past decade have greatly improved our comprehension of the pathogenesis and risk factors associated with Spondyloarthritis (SpA). In addition, they have contributed to the advancement of novel therapeutic approaches. Although genetics still represents the primary risk factor for SpA, increasing evidence presented in this review suggests that environmental factors—such as air pollution, smoking, gut microbiota (GM), infections, and diet—also contribute to its pathogenesis. In detail, environmental particulate matters (PMs), which include ligands for the aryl hydrocarbon receptor—a cytosolic transcription factor responsive to toxic substances—facilitate the differentiation of T Helper 17 (Th17) cells, potentially exacerbating the autoinflammatory processes associated with SpA. Furthermore, smoking influences both the cellular and humoral aspects of the immune response, resulting in leukocytosis, impaired leukocyte functionality, and a decrease in various cytokines and soluble receptors, including interleukin (IL) 15, IL-1 receptor antagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R), as well as the vascular endothelial growth factor (VEGF) receptor. Studies have indicated that patients with SpA exhibit an increased prevalence of antibodies directed against a conserved epitope shared by the human leukocyte antigen B27 (HLA-B27)- and Klebsiella nitrogenase, in comparison to HLA-B27-positive controls. Additionally, current evidence regarding the GM suggests the presence of a gut–joint–skin axis, wherein the disruption of the mucosal barrier by specific bacterial species may enhance permeability to the gut-associated lymphoid tissue (GALT), resulting in localized inflammation mediated by Th1 and Th17 cells, as well as IL-17A. Finally, this review discusses the role of diet in shaping the microbial composition and its contribution to the pathogenesis of SpA. A comprehensive understanding of the mechanisms by which environmental factors influence the pathogenesis and progression of the disease could facilitate the development of novel personalized therapies targeting both external and internal environmental exposures, such as the gut microbial ecosystem. Full article

The high variability of human leukocyte antigen (HLA) genes results in each molecule having distinct antigenic peptide binding capacities, potentially influencing the immune response to SARS-CoV-2. This study aimed to investigate associations between HLA class I (A, B) and class II (DRB1) polymorphisms and COVID-19 severity in a South Brazilian population, and to evaluate the binding affinity of alleles to viral peptides. A cross-sectional study included 503 unvaccinated patients with RT-qPCR-confirmed COVID-19: 145 non-severe, 129 severe, and 229 critical. HLA typing was performed using PCR-SSO and Luminex™ technology. The DRB1*11 allelic group was significantly associated with protection against severe and critical cases, while DRB1*15 was associated with increased risk; both remained significant after Bonferroni correction. Other allelic groups were associated with disease outcomes but lost significance after correction: B*49 and B*08 (risk); and B*37, B*50, and A*03 (protection). In silico analysis revealed that the DRB1*15 allele group showed a higher proportion of strong binders, mostly from non-structural proteins, while DRB1*11:01 binders, though fewer in number, were concentrated in the M protein. These results suggest functional differences in antigen presentation and reinforce the relevance of class II HLA, particularly DRB1, in modulating COVID-19 severity. Full article