Search Results (1,667)

Background: Systemic autoinflammatory phenotypes can clinically overlap with Familial Mediterranean Fever and other monogenic autoinflammatory diseases, yet some cases remain unclassified in the absence of pathogenic variants in MEFV or other related genes. In this study, we aimed to investigate the genetic and molecular basis of an unclassified autoinflammatory phenotype in a two-generation family comprising four affected members and one unaffected member. Methods: We performed whole-exome sequencing in all family members and prioritized variants according to rarity, predicted functional impact, segregation pattern, and biological relevance to inflammatory pathways. Downstream molecular analyses were performed using PBMCs from affected individuals and the unaffected family member. Results: Whole-exome sequencing identified a novel splice-site variant in PSMB10 (NM_002801; c.56+1G>A) affecting the canonical splice donor site. The variant segregated with the autoinflammatory phenotype and was associated with reduced full-length PSMB10 transcript levels in patient-derived PBMCs, supporting a predicted loss-of-function effect. Although pathogenic variants in PSMB10 have previously been implicated in proteasome-associated autoinflammatory syndrome (PRAAS), the clinical presentation in this family differed from the classical PRAAS phenotype. Molecular analyses showed altered immunoproteasome-related gene expression and a severity-associated interferon-related response. Severely affected individuals showed increased expression of interferon-related genes, including ISG15, IFI35, and SIGLEC1, whereas mildly affected individuals showed lower or reduced expression patterns. Notably, the extent of these molecular alterations differed among family members and broadly reflected the observed clinical heterogeneity. Conclusions: We report a novel PSMB10 splice-site variant as a strong potential contributor to an unclassified autoinflammatory disease, with a predicted disruption of canonical splicing and loss of protein function. Our findings expand the clinical spectrum of immunoproteasome-associated disorders and suggest that immunoproteasome-related dysregulation and variable interferon responses may contribute to disease severity. The intrafamilial variability observed in this family suggests that additional genetic or immunogenetic factors may modify disease expression, even in autoinflammatory disorders that appear to follow a monogenic inheritance pattern. Full article

Human metapneumovirus (hMPV) is an important respiratory pathogen and a major cause of respiratory tract infections, particularly among vulnerable populations. Although hMPV was identified in 2001, it remains less extensively studied than other major respiratory viruses, such as influenza virus and respiratory syncytial virus (RSV), hindering the development of effective preventive and therapeutic strategies. This review examines the primary mechanisms by which hMPV evades host immune responses. The virus disrupts early innate immune signaling pathways, particularly those involved in the induction and signaling of antiviral interferons (IFNs) and modulates inflammatory responses. At the level of adaptive immunity, hMPV impairs T-cell activation and the development of long-lasting immunological memory, which may contribute to susceptibility to reinfection. The virus also alters the functions of several immune and structural cell types, including macrophages, dendritic cells, and respiratory epithelial cells. In addition, hMPV may modulate host microRNA expression to promote immune evasion and prolong infection. The recurrent nature of hMPV infections highlights the need to further investigate the immune-evasion mechanisms. Such research is essential for developing safer and more effective vaccines, antiviral agents, and immunomodulatory therapies. Full article

Background: Elite HIV controllers exhibit persistent immune activation despite sustained viral suppression, a phenomenon that challenges the traditional view of immunological equilibrium. In parallel, autoimmune diseases are characterised by chronic inflammation driven by dysregulated immune responses. Objective: This study aimed to analyse the potential pathophysiological convergence between both conditions and to identify a shared inflammatory axis with possible translational implications. Methods: A critical narrative and integrative reflection was conducted using a purposive, concept-driven selection of evidence from PubMed/MEDLINE, Scopus, and Web of Science. A total of 43 sources were included: 28 studies informing mechanistic findings (14 on elite HIV controllers and 14 on autoimmune diseases), 12 addressing modulatory strategies (pharmacological and lifestyle-based), and 3 providing contextual frameworks. Results: Both conditions demonstrate sustained activation of innate immunity, characterised by elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF, type I interferons), increased inflammatory biomarkers (e.g., sCD14, IP-10), and activation of pathways such as NLRP3 inflammasome and NF-κB signalling. Collectively, these findings suggest convergence towards a potential shared inflammatory axis mediated by the inflammasome–interferon pathway, which may contribute to persistent systemic inflammation and tissue damage. Evidence from pharmacological and non-pharmacological interventions suggests that components of this axis may be susceptible to modulation. Conclusions: The observed convergence supports a conceptual model of shared innate inflammatory activation across both conditions. Rather than implying a unified therapeutic approach, the findings suggest a framework of convergent modulation targeting the inflammasome–interferon axis. This hypothesis warrants further investigation to determine its clinical and translational relevance. Full article

In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered “foreign”. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Zα) domains and couples recognition of these conformational states to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer’s disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA–RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3–MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis. Full article

Interferons (IFNs) are a family of cytokines which serve as the first line of defense against pathogen infections while also exerting critical immunomodulatory roles. IFNs can induce hundreds of IFN-stimulated genes (ISGs) with cell-specificity, yet a high-resolution comparison of time-serial ISG induction across cell types is lacking. By using RNA sequencing, we conducted a comparative transcriptomic profiling during time-serial IFN-γ stimulation for up to 24 h in HeLa and HEK293T cells, the two most widely used immortalized human cell lines. We uncovered remarkably stronger IFN responses in HeLa cells, regarding the global transcriptomic dynamics, the number of induced ISGs, and the level of ISG expression. Both cell lines share a core set of ISGs associated with canonical JAK-STAT signaling, yet HeLa uniquely activates additional inflammatory and adaptive immunity-related pathways. Despite the much weaker IFN response in HEK293T cells, we also identified a few HEK293T-specific ISGs, including several with crucial immune-related functions. Notably, transposable elements—including many adjacent to ISGs—are also highly up-regulated in HeLa cells, implying their potential links to ISG induction. Collectively, this study provides a high-resolution temporal atlas of IFN-γ-stimulated transcriptomic dynamics in HeLa and HEK293T cells, revealing the shared core module and cell-specific patterns of their interferon responses. Full article

The porcine interferon (IFN) system is highly diversified, particularly within Type I subfamilies, yet its evolutionary trajectory across domestication and breed formation remains poorly characterized. We performed a comprehensive comparative genomic and structural analysis of 432 IFN sequences spanning all IFN types across 11 Sus scrofa breeds representing commercial, indigenous, and wild/outgroup lineages. Phylogenetic reconstruction, pairwise dN/dS selection pressure analysis, and AlphaFold2-based 3D structure prediction coupled with DALI structural similarity mapping were integrated to resolve repertoire architecture, evolutionary constraints, and domestication-associated divergence. IFN repertoire organization is governed primarily by family identity rather than breed origin, with Type I IFN-α, -δ, and -ω subfamilies showing pronounced gene expansion in domestic breeds. Phylogenetic clustering and structural similarity consistently grouped sequences by subtype, independent of domestication history. Pervasive purifying selection (median ω = 0.48) maintained functional constraints across all lineages. Commercial breeds exhibited significantly higher within-category structural convergence alongside expanded repertoires, while structural conservation was evolutionarily decoupled from sequence-level selective pressure. Domestication potentially drove coordinated IFN repertoire expansion and structural conservation with related purifying selection at the gene level. These findings establish a genomic framework linking breed-specific IFN architecture to antiviral capacity and provide a foundation for immunogenetic-informed breeding strategies in the swine model. Full article

Sjögren’s disease (SjD) is a systemic autoimmune disease characterized by exocrine dysfunction, lymphocytic infiltration of the exocrine glands, and prominent activation of the interferon (IFN) pathway. Although IFN signatures are recognized as a central feature of SjD, endogenous triggers that sustain chronic IFN-driven inflammation remain incompletely understood. Mitochondrial RNAs (mtRNAs), particularly double-stranded species, have recently emerged as immunostimulatory molecules capable of linking mitochondrial stress to innate immune activation. In this review, we discuss the biological basis of mtRNA biogenesis and processing, the formation and mislocalization of mitochondrial double-stranded RNAs, and their recognition by innate immune sensors relevant to induction of type I IFN. We also describe how epithelial stress, mitochondrial dysfunction, and mtRNA accumulation amplify IFN-rich inflammatory circuits and glandular injury in SjD. Experimental studies in salivary gland epithelial models and SjD-relevant tissues support a mechanistic role for the mtRNA–type I IFN axis, while emerging clinical data suggest that extracellular mtRNA levels in saliva and plasma may have potential as biomarkers of disease activity and patient stratification. Although current evidence remains limited, the mtRNA–type I IFN axis provides a biologically plausible link between epithelial stress and immune dysregulation, and may have translational implications in SjD. Full article

Background/Objectives: Glioblastoma (GBM) is the most lethal primary brain malignancy in adults, with a median overall survival of approximately 15 months. Temozolomide (TMZ) resistance develops in virtually all patients, and no second-line regimen has improved outcomes over the past two decades. The DNA methyltransferase inhibitor decitabine (DAC) has attracted interest as a chemosensitizer, but whether it directly reverses the TMZ-resistance transcriptome or operates through distinct, complementary mechanisms has not been tested at multi-omics resolution. Methods: We performed an integrative six-layer multi-omics analysis across five public GEO datasets (bulk RNA-seq, EPIC 850K methylation, and 21,676 single cells) re-purposed from studies conducted for unrelated aims, formally tested DAC-mediated reversal of the TMZ-resistance transcriptome across 11,707 genes, mapped pharmacogenomic targets with DGIdb v5, and built an exploratory, hypothesis-generating 11-gene prognostic model internally validated in TCGA-GBM (n = 166) and externally tested in the independent CPTAC-GBM cohort (n = 96). Results: DAC reprogrammed transcription across 1114–1882 differentially expressed genes per cohort and reactivated 146 direct epigenetic targets, identifying INPP5D/SHIP1 as the top-ranked direct epigenetic-reactivation target. Genome-wide reversal analysis across 11,707 co-detected genes showed a negligible effect (Spearman ρ = 0.073), but single-cell analysis revealed significant per-cell attenuation of MES-like and stem-like programs (Δ = −0.071 and −0.135, respectively; both p < 0.001). The 11-gene risk model achieved a Harrell’s C-index of 0.706 (apparent); after correcting for the two-stage gene selection with a full-pipeline bootstrap, the optimism-corrected C-index was 0.63, and external validation in an independent cohort (CPTAC-GBM, n = 96) showed only near-chance discrimination (C-index 0.55), indicating that the signature does not generalize and is exploratory. Pharmacogenomic mapping yielded 734 unique therapeutic agents (230 FDA-approved) across 69 druggable targets after excluding AR. Most of these agents are not GBM-directed, so this catalog-level mapping is hypothesis-generating rather than a set of therapeutic recommendations. Conclusions: DAC does not broadly reverse the TMZ-resistant transcriptome but acts through three complementary mechanisms: epigenetic reactivation of INPP5D/SHIP1, cancer-testis-antigen and type I interferon induction, and per-cell attenuation of mesenchymal–stem-like transcriptional intensity, supporting hypotheses for rationally designed DAC-based combination therapy in TMZ-resistant GBM. Full article

Equine herpesvirus type 1 (EHV-1) is a major cause of reproductive loss in mares. This cross-sectional field study evaluated serum concentrations of interleukin-2 (IL-2), interleukin-10 (IL-10), interferon-alpha (IFN-α), and interferon-gamma (IFN-γ), together with the IL-10/IL-2 and IFN-γ/IL-10 ratios, in 26 vaccinated pregnant Thoroughbred mares. The analytical cohort comprised healthy, EHV-1 PCR-negative mares (HM, n = 10), EHV-1 PCR-positive mares sampled within 4 h after fetal expulsion at approximately the sixth month of gestation (AM, n = 9), and EHV-1 PCR-positive pregnant mares without clinically relevant signs (WCS, n = 7). EHV-1 DNA was detected using an EHV-1-specific real-time PCR assay, and serum cytokine concentrations were measured using equine-specific ELISA kits. Serum IFN-α, IFN-γ, and IL-2 concentrations were significantly higher in both AM and WCS mares than in HM mares (all Holm-adjusted p < 0.001), whereas no statistically significant differences in these cytokines were observed between the AM and WCS groups. IL-10 concentrations were significantly higher in WCS mares than in both HM and AM mares (both adjusted p < 0.01), and HM and AM mares did not differ significantly. The IL-10/IL-2 ratio was highest in HM mares, intermediate in WCS mares, and lowest in AM mares, with significant differences among all pairwise comparisons (adjusted p ≤ 0.019). Conversely, the IFN-γ/IL-10 ratio was highest in AM mares, intermediate in WCS mares, and lowest in HM mares, again with significant differences among all pairwise comparisons (adjusted p ≤ 0.044). These findings indicate substantial antiviral immune activation in both EHV-1-positive groups, with a comparatively stronger regulatory immune component in WCS mares and a predominantly pro-inflammatory profile in mares sampled after abortion. Full article

Patients with autoimmune rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), experience excess cardiovascular risk that is not fully captured by conventional lipid measurements. In active RA, lower cholesterol may coexist with higher vascular risk, a pattern known as the lipid paradox. We propose that systemic inflammation can uncouple lipid concentration from lipoprotein function and organize the evidence along five mechanistic axes. Inflammatory cytokines, mainly interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1β, IL-17/IL-23 and type I interferons, remodel lipoprotein metabolism. High-density lipoproteins (HDL) lose protective functions and may become pro-inflammatory. Apolipoprotein-B particles are oxidized or otherwise modified, linking lipid metabolism to autoimmunity. Macrophage cholesterol imbalance and cholesterol crystals activate inflammasome pathways in experimental atherosclerosis, while immune-cell metabolic rewiring may amplify cytokine output; these mechanisms are treated as extrapolated when direct rheumatic-disease evidence is limited. The pathways converge on endothelial dysfunction and thrombo-inflammation. RA and SLE are the mechanistic anchors, whereas psoriatic disease, axial spondyloarthritis, systemic sclerosis, vasculitides and antiphospholipid syndrome are weighted by evidence category. Standard lipid panels may therefore underestimate risk in selected contexts, especially during active inflammatory disease. Full article

Spring viremia of carp virus (SVCV) poses a major threat to aquaculture industry, triggering severe economic losses and substantial damage to fish health. Effective antiviral therapeutic approaches are currently insufficient in aquaculture, highlighting an urgent demand for viable intervention strategies. This study assessed the antiviral and immunomodulatory potential of Houttuynia cordata against SVCV in common carp. Combined cellular and in vivo fish experiments demonstrated that Houttuynia cordata markedly suppresses SVCV replication, reduces viral titer, and enhances disease resistance of carp. The extract appears to suppress RARα-A, upregulate IFN-1/CXCL11, and recruit T lymphocytes via CXCL11, thereby enhancing innate and adaptive immunity against SVCV. Experimental results indicate that Houttuynia cordata alleviates hemorrhagic symptoms induced by SVCV infection. Dietary supplementation with this herb realizes dual functions of viral suppression and immune regulation for carp aquaculture. The findings provide a practical prevention and control strategy against SVCV infection and offer novel insights for research on green antiviral agents. Furthermore, this study verifies the potential value of Houttuynia cordata in improving biological safety and facilitating sustainable development of aquaculture, laying a solid foundation for the development of eco-friendly antiviral preparations. Full article

Proteins and associated post-translational modifications are receiving deserved attention in the search for immune therapies to combat a long list of diseases, including a number of fatal forms of cancer. Such attention has been fueled by a number of clinical results generated by numerous clinical trials, together with datasets generated by academic research. The title of this review is based on a couple of considerations: most, if not all, researched immune checkpoints are proteins, each of which can experience one or more post-translational modifications (PTMs). It is also known that among the main functions of post-translational modifications is their direct impact on protein localization. Given that most activities of known checkpoints are performed on the surface of the host cells, post-translational modifications are bound to influence the role of these proteins, both as drivers of various diseases and as therapeutic targets. The second consideration concerns another class of proteins, which is responsible for a severe toxic reaction in the immune system following treatment with immune cell inhibitors, a reaction known as cytokine release syndrome (CRS). Cytokines are low-molecular-weight proteins, among which the key members are interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon γ (IFN-γ). A number of clinical trials have shown that the symptoms of CRS toxicities are frequently accompanied by elevated levels of cytokines, including IL-6 and IFN-γ. The recent literature suggests that we still need to know more about the biology of these proteins and the type of modifications that these key members of cytokines can experience. Such additional knowledge may contribute to more effective and safer immune cell therapy. The contribution of mass-spectrometry-based proteomics to the investigation of PTMs associated with immune checkpoints and cytokines is discussed. Full article

Individual responses to SARS-CoV-2 vaccination vary due to viral mutations, demographic factors, and genetic background, with T-cell responses being less affected by viral variability. However, less is known about the effect of age, sex, and genetic background on the T-cell response in vaccinated subjects. In particular, the influence of interferon lambda (IFN-λ) genetic polymorphisms on vaccine-induced cellular immunity has been poorly explored. Here, we assessed intracellular production of IFNγ, TNFα, and IL-2 in CD4⁺ and CD8⁺ T cells stimulated with SARS-CoV-2 spike peptides from 50 vaccinated subjects genotyped for IFNL3 (rs12980275 and rs8099917) and IFNL4 (rs11322783TT and rs12979860) SNPs. We found that the IFNL4 rs11322783TT/TT genotype is associated with increased IL-2 production in CD8⁺ T cells, whereas the ΔG allele correlates with a reduced IL-2 response. No significant effects on CD4⁺ T-cell cytokine production or other cytokines were observed. These preliminary findings suggest that type III interferon gene variants might be involved in CD8⁺ T-cell responses post-vaccination, opening the possibility that evaluation of IFNL4 SNPs might be useful in designing strategies of personalized vaccination. Full article

Sjögren’s disease (SjD) is a chronic autoimmune disease characterized by lymphocytic infiltration and dysfunction of the exocrine glands, with manifestations extending beyond glandular sicca symptoms to multiple extraglandular systems. Although the pathogenesis of SjD remains incompletely understood, growing evidence indicates that a complex cytokine network involving both innate and adaptive immune pathways plays a central role in disease development. This narrative review summarizes recent updates on cytokine signaling in SjD across three clinically relevant domains. In glandular inflammation, activation of salivary gland epithelial cells through Toll-like receptor pathways triggers type I interferon (IFN) signaling via plasmacytoid dendritic cells, while IFN-γ, Th17-related cytokines (IL-6, IL-17, IL-22), BAFF/APRIL, and chemokines (CXCL10, CXCL12, CXCL13) collectively sustain local inflammation and ectopic lymphoid organization. The BAFF/APRIL axis, a systemic type I IFN signature, and IL-21–follicular helper T cell–B cell interactions primarily drive systemic immune activation, which together underlie autoantibody production, hypergammaglobulinemia, and a lymphoma-prone phenotype. In contrast, constitutional symptoms such as fatigue, pain, and dryness frequently dissociate from classical inflammatory activity and are better explained by neuroimmune–metabolic mechanisms, including the IFN-γ–IDO–kynurenine pathway and symptom-associated proteomic signatures. Collectively, these findings underscore the heterogeneous nature of SjD, in which glandular inflammation, systemic immune activation, and constitutional symptoms are driven by distinct yet partially overlapping cytokine pathways. Recognizing this heterogeneity has direct implications for cytokine-targeted therapy, suggesting that future trials should stratify patients by disease phenotype (IFN-high, B cell-dominant, and symptom-dominant) rather than treating SjD as a uniform population. Full article

Multiple myeloma (MM) remains an incurable hematological malignancy in which tumor-intrinsic immune evasion limits the efficacy of immunotherapy. Here, we identify the RNA editing enzyme ADAR1 as a key regulator of innate immune suppression in MM. Integrative analyses of bulk and single-cell transcriptomic datasets, together with clinical validation, demonstrated that ADAR1 is upregulated in malignant plasma cells and is associated with adverse clinical outcomes and reduced CD8⁺ T-cell infiltration. Mechanistically, ADAR1 knockdown increased the association of endogenous dsRNA with melanoma differentiation-associated protein 5 (MDA5), restoring type I interferon (IFN) signaling, enhancing IFNα production and STAT1 activation, and promoting CD8⁺ T-cell proliferation and cytotoxic function. These effects were largely abolished by MDA5 depletion, establishing a functional ADAR1–MDA5 signaling axis in MM. In vivo, treatment with 8-azaadenosine significantly potentiated the antitumor efficacy of PD-1 blockade, resulting in reduced tumor growth, increased tumor cell apoptosis, elevated IFNα expression, and enhanced CD8⁺ T-cell infiltration. Together, our findings demonstrate that ADAR1-mediated RNA editing enables immune evasion by restricting MDA5-dependent sensing of endogenous dsRNA and highlight the ADAR1–MDA5-type I interferon axis as a promising therapeutic target for improving immunotherapy in multiple myeloma. Full article