Search Results (635)

Transcription factor 19 (TCF19) is a multifunctional biomolecule located within the major histocompatibility complex (MHC) class I region on chromosome 6p21.3. Structurally, TCF19 contains a plant homeodomain (PHD) finger that recognizes histone H3 lysine 4 trimethylation (H3K4me3) and a forkhead-associated (FHA) domain with yet-uncharacterized functions. Emerging evidence positions TCF19 as a multifunctional regulator associated with cell cycle progression, transcriptional regulation, cancer progression, and immune modulation through epigenetic and signaling mechanisms. This review provides the first systematic synthesis of TCF19’s structural domains, regulatory networks, and context-dependent functions across cancer and non-cancer diseases. We highlight critical knowledge gaps, including the unresolved function of its FHA domain and the lack of direct small-molecule inhibitors. In cancer, TCF19 drives proliferation, metastasis, immune evasion, and therapy resistance. Beyond cancer, TCF19 is involved in metabolic diseases, chronic infections, inflammatory disorders, and sensory deficits. TCF19 serves as a promising molecular biomarker for cancer diagnosis, prognosis, and treatment response monitoring, though direct targeting strategies remain unavailable. Full article

Background: Idiopathic inflammatory myopathies (IIMs), characterized by muscle weakness and chronic inflammation, currently lack highly effective therapies. This study investigated the therapeutic potential and underlying mechanism of (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative with reduced toxicity, using an experimental autoimmune myositis (EAM) mouse model and in vitro assays. Methods: Forty female BALB/c mice were randomly assigned to five groups: normal, vehicle, methylprednisolone (MP), LLDT-8 (0.0625 mg/kg), and LLDT-8 (0.125 mg/kg). EAM mice were treated with LLDT-8 (0.0625 or 0.125 mg/kg) or methylprednisolone as a positive control. Cellular experiments and molecular docking were performed to investigate potential mechanisms of LLDT-8. Results: LLDT-8 significantly attenuated clinicopathological features, including muscle weakness and pain sensitivity, while reducing serum levels of aspartate aminotransferase and lactate dehydrogenase. Histological analysis revealed that LLDT-8 reduced inflammatory cell infiltration and the presence of CD4⁺ and CD8⁺ T cells in muscle tissues. Mechanistically, LLDT-8 inhibited the expression of nucleotide-binding oligomerization domain receptor caspase recruitment domain 5 (NLRC5), a key transcriptional regulator of major histocompatibility complex-I (MHC-I). This suppression extended to downstream antigen presentation-related molecules, including the transporter associated with antigen processing and proteasome 20S subunit beta. Molecular docking further confirmed the high binding affinity of LLDT-8 to both NLRC5 and MHC-I. Conclusions: LLDT-8 alleviates inflammatory muscle injury by targeting the NLRC5/MHC-I signaling axis, suggesting it may be a promising therapeutic candidate for IIMs. Full article

Type 1 diabetes (T1D) is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic β-cells. Antigen-specific peptide immunotherapy represents a promising strategy to restore immune tolerance. Reliable identification of relevant T-cell epitopes requires accurate prediction of peptide binding to disease-associated major histocompatibility complex (MHC) molecules. In this study, we developed and validated artificial intelligence (AI)-driven machine learning (ML) predictive models for peptides binding to the NOD mouse-specific MHC class I molecules H-2D^b and H-2K^d and the class II molecule I-A^g7. Balanced datasets of experimentally validated binders and non-binders were compiled, divided into training and test sets, and used to construct position-specific logo models and supervised ML classifiers based on z-scale physicochemical descriptors. External validation demonstrated moderate predictive performance for the logo models (ROC AUC 0.685–0.738), whereas AI models, including Random Forest, Support Vector Machine, and Gradient Boosting, achieved substantially improved discrimination (ROC AUC 0.888–0.906). The validated models were applied to the major T1D autoantigens glutamic acid decarboxylase 65, insulin-1, insulin-2 and zinc transporter 8 and predicted multiple binders, with some overlapping with previously reported immunodominant regions. Selected binders were prioritized for further synthesis and in vivo immunogenicity testing in NOD mice. Full article

The antigen presentation machinery processes proteins for presentation to T cells, thereby controlling activation of the adaptive cellular immune response. Perturbation of this machinery has been linked to the development of various diseases. This review describes the function of the Major Histocompatibility Complex class I antigen presentation machinery and highlights how its perturbation can lead to compromised immune function and disease progression in the context of cancer. We categorize these perturbations into four distinct mechanistic levels: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. This enables an integrated view of their functional impact on immune recognition, supporting therapeutic efforts to target antigen presentation or exploit these alterations in cancer. Full article

Avian influenza (AI) continues to threaten global poultry production, with accumulating evidence suggesting that certain commercial layer lines may exhibit increased susceptibility under specific experimental conditions compared with broiler chickens. This narrative review synthesizes published experimental infection studies identified through a comprehensive PubMed search, focusing on low pathogenic H9N2 and highly pathogenic H5N1, H5N2, H7N7, and H7N9 viruses. Although bird age and production stage varied across studies, consistent disparities in immune regulation and viral replication dynamics have been reported. We critically evaluate host determinants underlying these differences—including microRNAs, major histocompatibility complex polymorphisms, sialic acid receptor distribution, gut microbiota, and hormonal influences—and integrate findings across viral subtypes and pathogenicity classes to inform breed-tailored vaccination, nutritional, and therapeutic strategies. Full article

Muscle biopsy (MB) is an important tool to help differentiate idiopathic inflammatory myopathies (IIMs) from hereditary muscular diseases (HMDs). The usefulness of immunohistochemical stains of the major histocompatibility complex class I and the membrane attack complex are controversial, as both may be identified in some HMDs. More sensitive markers of IIMs have recently been used, such as myxovirus resistance A (MxA), a type I interferon-inducible protein. We selected skeletal MB samples from 81 patients diagnosed with IIM and HMD harbouring overt inflammatory infiltrates on their MBs in the period between March 2022 and September 2024. Two groups were identified: the IIM group (46 cases) and the HMD group (35 cases). We characterized and compared the patterns of MxA protein expression among the two groups. In the IIM group, positive sarcoplasmic MxA expression was detected on the myofibres of 10 patients (24%), among whom were eight dermatomyositis patients. In the HMD group, we did not identify any sarcoplasmic positivity. However, five patients (14%) showed positive labelling restricted to the sarcolemmal membrane, including non-necrotic or regenerating fibres. Our study demonstrates the value of MxA for increasing dermatomyositis diagnostic accuracy and suggests the potential role of interferon type I in the pathophysiology of HMD. Full article

Cancer immunotherapy has transformed the clinical management of several malignancies; however, its efficacy remains limited in tumors with low mutational burden and restricted availability of classical mutation-derived neoantigens. In this context, increasing evidence indicates that the tumor immunopeptidome extends far beyond canonical protein-coding regions, incorporating peptides derived from non-coding transcripts through non-canonical translation mechanisms. Long non-coding RNAs (lncRNAs), traditionally regarded as transcriptional or post-transcriptional regulators, have recently emerged as an unexpected source of small open reading frame-encoded peptides (lncPEPs). A subset of these peptides is processed and presented by major histocompatibility complex class I molecules, generating tumor-specific neoantigens capable of eliciting CD8⁺ T cell responses. Owing to the high tissue and context specificity of lncRNA expression, lncRNA-derived neoantigens offer unique advantages over mutation-based targets, including increased tumor selectivity and potential recurrence across patient subsets. In this review, we synthesize current knowledge on the biogenesis, detection, and immunogenic potential of lncRNA-derived peptides, highlighting experimental and computational strategies for their identification within the cancer immunopeptidome. We discuss the challenges associated with their validation and clinical translation, as well as their relevance for the development of vaccines and adoptive T cell–based therapies. Finally, we illustrate these concepts using epithelial ovarian cancer as a representative model of low-mutational-burden tumors, where lncRNA-derived neoantigens may help overcome current limitations of immunotherapy and enable patient stratification for personalized treatment approaches. Full article

The porcine epidemic diarrhea virus (PEDV) causes a gastrointestinal disease generating mortality rates approaching 100% in piglets worldwide. The S glycoprotein of PEDV is the main target for the development of vaccines. Two vaccines approved by the Ministry of Agriculture and Rural Development are used in Mexico: the first vaccine is based on an inactivated virus isolated more than a decade ago, whereas the second vaccine is based on mRNA technology. The most important tool for controlling PEDV outbreaks is vaccination; however, coronaviruses are characterized by the accumulation of multiple mutations, which compromise the immune response elicited by outdated vaccines. In this work, we classified the Mexican strains of PEDV reported so far in GenBank, according to their genotypes. Subsequently, we searched for B and T cell epitopes conserved in Mexican PEDV strains using bioinformatic tools. In addition, we explored whether these epitopes can induce allergies, autoimmunity, and/or toxic effects. Next, we determined the localization of B cell epitopes in the S glycoprotein using the protein crystal and protein modeling of several S glycoproteins. Finally, we carried out molecular docking analysis to assess whether these T cell epitopes could interact with the peptide-binding groove of the Swine Leukocyte Antigens (SLAs). Five conserved B cell epitopes were found to be exposed on the surface of the S glycoprotein, whereas several promiscuous CTL and HTL epitopes were bound, with low free energy, to the peptide-binding grooves of SLA-I and SLA-II, respectively. The best epitopes were used to generate a plasmid carrying the sequence to produce a recombinant protein. This plasmid was used for transfection experiments in PK-15 cell culture. The B cell epitopes reported here were recognized by the sera from pigs infected with PEDV but not by the sera from uninfected animals. These results justify future evaluations of the ability of these epitopes to stimulate cytokine production by T cells, antibody generation, and their neutralizing activity. Full article

Background: Dry Eye Disease (DED) is a multifactorial disorder characterized by tear film instability and ocular surface inflammation. Murine models based on environmental stress are widely used to mimic evaporative DED, although many focus on limited disease features. This study aimed to provide an integrated characterization of ocular surface alterations induced by chronic desiccating stress. Methods: Adult mice were housed in a Controlled-Environmental Chamber (CEC) with low humidity and increased airflow for up to 21 days and sacrificed after 14 or 21 days. Corneal damage was assessed by fluorescein staining. Conjunctival histology was evaluated for epithelial morphology, goblet cell (GC) size, and mucin composition. Complement fractions C3 and C5a were assessed by immunohistochemistry. Expression of inflammatory markers (Major Histocompatibility Complex, Class II, DR, HLA-DR; interleukin-1β, IL-1β; tumor necrosis factor-α, TNF-α) was quantified by Real-Time PCR (RT-PCR) in corneal and conjunctival epithelium. Results: Fluorescein staining revealed progressive corneal epithelial damage over time. Histological analysis demonstrated conjunctival epithelial alterations characterized by a significant reduction in GC size and in neutral mucin-positive GCs, consistent with mucin remodeling of the ocular surface epithelium. Increased epithelial deposition of complement fractions C3 and C5a was observed, while molecular analysis confirmed upregulation of inflammatory markers, including HLA-DR, IL-1β, and TNF-α. Collectively, these findings indicate that the model captures key pathophysiological components of DED. Conclusions: The CEC model reproduces major features of evaporative DED, including epithelial damage, GC remodeling, immune activation, and inflammation. As a non-invasive desiccating stress model, it represents a relevant experimental platform for studying ocular surface inflammation and for preclinical evaluation of therapeutic strategies. Full article

Background: B-cell malignancies have been effectively treated using chimeric antigen receptor-T (CAR-T) treatment employing traditional αβT cells. However, because of several obstacles, application in acute myeloid leukemia (AML) is still restricted. A safer “off-the-shelf” alternative can be supplied by CAR-γδT cells, which have major histocompatibility complex (MHC)-independent tumor identification capabilities and a decreased risk of graft versus host disease (GvHD). This study aimed to develop FLT3-targeted CAR-γδT cells that co-express cytokines (IL-2 or IL-7) to increase their anti-AML persistence and therapeutic efficacy. Methods: FLT3-CAR-γδT cells, FLT3-IL2-CAR-γδT cells, and FLT3-IL7-CAR-γδT cells were constructed. Their antitumor potency was comprehensively assessed through cytotoxicity assays, cytokine release, and persistence evaluation in vitro (using AML cell lines and primary AML cells) and in vivo (via mouse model). Results: Superior cytotoxicity against AML cell lines (OCI-AML3, MOLM-13, THP-1, and MV4-11) was demonstrated by FLT3-IL2-CAR-γδT cells, which also released higher levels of granzyme B, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). FLT3-IL2-CAR-γδT cells exhibited cytotoxicity in some primary AML cells in vitro. During the antigen-repeated stimulation assay, FLT3-IL2-CAR-γδT cells preserved the stem cell-like memory T (T_SCM) cell subsets, sustained cytokine release, and maintained excellent viability. FLT3-IL2-CAR-γδT cells considerably slowed the development of AML in vivo and extended the existence (>68 days) of mice. Conclusions: FLT3-IL2-CAR-γδT cells exhibit potent and durable anti-AML activity, providing a novel strategy for clinical AML immunotherapy. Full article

Beta-2-microglobulin (B2M) is a key component protein in the processing and presentation of major histocompatibility complex (MHC)-I antigens and plays an important role in the immune system regulation. Previous studies have shown that B2M is significantly overexpressed in the intestinal tissues of sheep that are resistant to E. coli F17b infection (defined by milder clinical symptoms post-challenge) compared to those that are susceptible (exhibiting severe diarrhea). Based on this finding, this study aimed to investigate whether B2M influences the adhesion of E. coli F17b to sheep intestinal epithelial cells (IECs) and to assess its role in regulating IEC proliferation and migration. We tested this by overexpressing and knocking down B2M in IECs, and then measured bacterial adhesion through colony counts and fimbrial gene expression (RT-qPCR). Moreover, cell health was assessed using proliferation (CCK-8 and EdU) and migration (scratch) assays. The results showed that upregulation of B2M expression inhibited E. coli F17b adhesion and promoted IEC proliferation and migration. Silencing B2M increased bacterial adhesion and impaired cell function. In summary, B2M helps protect sheep IECs from E. coli F17b by strengthening the epithelial barrier through improved cell growth, proliferation, and migration. These findings elucidate part of the host defense mechanism against E. coli F17b, providing a basis for further research. Full article

Background: Lung cancer and chronic obstructive pulmonary disease (COPD) are morbid and mortal conditions arising from noxious endothelial stress. Soluble Major Histocompatibility Complex I Chain Related A (sMICA) is an activating ligand for the NKG2C receptor, and the soluble form indicates endothelial stress and is a mechanism for evading immune surveillance in lung cancer. We provide independent associations between sMICA*008 levels and the prevalence of lung cancer, lung cancer histologies, COPD, and risk factors for both diseases. Methods: We describe statistical associations between sMICA and demographic and clinical variables. Multivariate linear regression determined the independent associations between sMICA levels and lung cancer histology, between those with and without primary lung cancer, and prevalent COPD in participants without lung cancer. Point estimates and 95% confidence intervals are reported; p < 0.05 is considered statistically significant. Results: The cohort (n = 586 patients) included 24% female and 48% current or former smokers. Mean sMICA were 5.20 pg/mL ×10², and FEV1%-predicted of 62. sMICA levels were higher in those who smoked vs. those who did not. In Multivariate regression, non-small cell lung cancer (NSCLC) was associated with 14.2 pg/mL ×10² (95% CI 3.57 to 24.9 pg/mL ×10²) higher sMICA levels compared to those without cancer. No other histology was independently associated with higher sMICA. Primary lung cancer [12.5 pg/mL ×10² (2.85 to 22.2 pg/mL ×10²)] and COPD in those without cancer [4.38 pg/mL ×10² (0.38 to 8.39 pg/mL ×10²)] were associated with higher sMICA. Conclusions: sMICA*008 is independently associated with NSCLC, primary lung cancer, and COPD, respectively, in a cohort of current, former, and never smokers with and without lung cancer. sMICA levels were also higher in smokers. This study provides a foundation for future studies on sMICA activity in lung cancer and COPD, and assessment of sMICA as a biomarker for lung cancer cell type and risk of lung function loss in COPD. Full article

Background. Inbred mouse models of autoimmune myocarditis are routinely used to investigate the immune mechanisms underlying dilated cardiomyopathy. However, their translational relevance is limited because observations made in a single inbred strain may not reflect those of outbred human populations. This limitation can be overcome by using Diversity Outbred (DO) mice, whose genetic variability is comparable to that of humans. Methods. To investigate the utility of DO mice, we characterized their immune cell distributions and induced myocarditis by immunization with porcine cardiac myosin (PCM) emulsified in complete Freund’s adjuvant. Antigen-specific T cell and antibody responses were evaluated using lymphocytes and serum samples, respectively, and hearts were examined histologically for inflammatory changes. Results. First, we noted no significant variations in the majority of immune cell populations, which include T cells and B cells. However, NK cells, double positive for CD49b and NK1.1, were lacking in both sexes. While we noted sex differences in the expression of major histocompatibility complex class II molecules in antigen-presenting cells, expression of costimulatory molecules was similar in both sexes. Second, upon immunization, we demonstrated that the PCM was immunogenic, and the PCM-reactive T cell responses were generated in both males and females, as measured by a proliferation assay. Third, cytokine analysis revealed marginal detection of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) cytokines, mainly with three doses of immunization. Fourth, determination of PCM-reactive antibody responses revealed significant amounts of IgG1 and IgG2b isotypes. Finally, histological analysis revealed varying degrees of myocarditis in individual mice of both sexes. Conclusions. Our data suggest that mild autoimmune myocarditis can be induced in DO mice. However, to capture the heterogeneity in disease susceptibility, large sample cohorts are required. Full article

Major histocompatibility complex class I chain-related gene A (MICA) is a non-classical MHC-I molecule essential for immune surveillance, yet its intracellular maturation remains poorly understood. We show that MICA is predominantly retained intracellularly in melanoma cells and colocalizes with the endoplasmic reticulum chaperone calreticulin (CRT). Notably, MICA also colocalizes with CRT in healthy skin. Immunoprecipitation assays reveal that CRT preferentially associates with a low-molecular-weight form of MICA. Recombinant protein assays and in silico analyses support direct interaction between CRT and non-glycosylated MICA, but not with fully glycosylated eukaryotic MICA. These findings identify CRT-dependent retention of MICA as a physiological checkpoint that may be dysregulated in melanoma to promote immune evasion. Full article

Eye drops derived from human blood components (Eye Drops of Human Origin—EDHO) have proven effective in reducing ocular pain associated with severe keratopathies. Among these, Cord Blood Serum (CBS) is particularly promising for its high content of growth and neurotrophic factors. This study evaluated the ability of CBS to modulate inflammatory and nociceptive activation in the human conjunctival epithelial cell (HCEC) line exposed to hyperosmotic stress. CBS batches were characterized for brain-derived neurotrophic factor (BDNF) content and classified as CBS_high (levels > 18.0 ng/mL) or CBS_low (levels < 10.0 ng/mL). HCECs were exposed to NaCl (450 mOsm/L) with or without 5% CBS. Cell viability was evaluated, and the expression of Major Histocompatibility Complex Class II (HLA-DR) (a marker of immune activation) and Transient Receptor Potential Vanilloid 1 (TRPV1) (a nociceptive ion channel responsive to osmotic stress) was assessed via Real Time PCR (RT-PCR). CBS significantly improved HCEC viability under hyperosmotic stress. Exposure to NaCl alone upregulated HLA-DR and TRPV-1 expression. Both CBS preparations attenuated these responses, producing comparable reductions in HLA-DR mRNA and decreasing TRPV-1 expression. Partial reversal of CBS effects by the pan-neurotrophin receptor inhibitor K252a supported neurotrophin involvement. CBS reduces hyperosmolarity-driven inflammation and nociception via HLA-DR and TRPV1 downregulation, supporting its role as a bioactive tear substitute in neuroinflammatory ocular surface disease. Full article