Network toxicology and multi-omics analyses identify diagnostic genes and elucidate underlying mechanisms of 6PPDQ-induced hepatocellular carcinoma.

Lactobacillus helveticus R0052-derived membrane vesicles ameliorate DSS-induced inflammatory bowel disease by modulating the gut microbiota and activating the cholinergic anti-inflammatory pathway.

Intervertebral disc degeneration (IVDD) is a major contributor to chronic spinal disorders, yet the role of endocytosis in its pathogenesis remains incompletely understood. In this study, we systematically investigated endocytosis‐related genes associated with IVDD by integrating bulk transcriptome data, single‐cell RNA sequencing datasets, and Mendelian randomization (MR) analysis. Differential expression analyses identified six ERGs consistently dysregulated in IVDD, among which HLA‐A and AP2M1 exhibited significant causal associations with disease risk in MR analysis and were further validated in independent datasets. Functional enrichment and gene set enrichment analyses indicated that these genes were closely involved in immune‐related pathways, including natural killer cell‐mediated cytotoxicity and mammalian target of rapamycin signaling. Immune infiltration analysis revealed marked alterations in macrophages, activated CD4+ T cells, and eosinophils in IVDD tissues, with strong correlations between immune cell proportions and the expression of HLA‐A and AP2M1. In vitro experiments demonstrated that overexpression of HLA‐A or AP2M1 promoted nucleus pulposus cell proliferation, suppressed apoptosis, and enhanced endocytic activity, whereas in vivo overexpression alleviated disc degeneration in a rat model. Collectively, these findings identify HLA‐A and AP2M1 as potential biomarkers linking immune dysregulation and endocytic dysfunction in IVDD and provide new insights into the molecular mechanisms underlying disc degeneration.

Background Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD), accelerates age-related decline in estimated glomerular filtration rate (eGFR), leading to a markedly increased prevalence of DKD among elderly diabetic patients. Recent studies suggest that immune dysregulation plays a pivotal role in DKD progression; however, the cellular and molecular mechanisms linking aging, immune infiltration, and DKD remain unclear. Methods We used single-cell RNA sequencing (scRNA-seq) analysis to characterize immune cell dynamics between the young, the elderly and DKD patients. Based on the scRNA-seq analysis, Mendelian randomization (MR) analysis of differentially expressed genes (DEGs) in CD8 + T cells were conducted to explore the casual relationship between DEGs and DKD. Results The CD8 + T cell cluster was the predominant T cell subtype, but its proportion gradually declined from young individuals to elderly subjects and DKD patients. MR analysis of DEGs in CD8 + T cells suggested that calcium/calmodulin dependent protein kinase 1D (CAMK1D) exhibited strongest causal relationship with DKD. CAMK1D was upregulated in DKD kidney tissues, and its expression was localized to CD8 + T cells, as confirmed by immunofluorescence staining. Functional analysis indicated that CAMK1D + CD8 + T cells engaged in pro-inflammatory and pro-fibrotic signaling with various renal cell types and showed enrichment in metabolic pathways related to DKD. Conclusion Our results highlighted the important role of CD8 + T cell in shaping the renal immune microenvironment in both DKD and aging. CAMK1D may serve as a shared molecular risk factor linking aging and diabetic renal injury.

Autoimmune thyroid diseases (AITDs) represent T cell-mediated, organ-specific autoimmune disorders caused by immune dysregulation, culminating in an immune-mediated attack on thyroid tissue. AITD etiopathogenesis is the result of the interplay between a genetic susceptibility and environmental factors; hypothyroidism and thyrotoxicosis are the respective clinical hallmarks of autoimmune thyroiditis and Graves’disease, the two main forms of AITD. The application of nanomedicine in the context of thyroid disorders ranges from nanodiagnosis and nanotherapy to nanotheranostics. Nanomedicine has been used to develop new sensitive methods for the determination of the TSH, iodine and TSAb. Furthermore, other studies have used nanomedicine to explore new treatments of autoimmune thyroiditis, Graves’disease and also thyroid eye disease. In the future, the application of nanomedicine will be personalized in accordance with individual genetic profiles, thus improving the therapeutic effectiveness and reducing the undesirable side effects with improved patient outcomes.

Background: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency, associated with recurrent infections, immune dysregulation, and non-infectious complications. Amyloidosis is a rare but severe complication with pulmonary involvement being exceptional. Objective: The aim of this study was to review reported cases of amyloidosis complicating CVID and present a unique case of pulmonary involvement. Methods: A literature research identified observational studies and case reports linking amyloidosis with CVID. Additionally, we describe a patient with CVID complicated by pulmonary and gastrointestinal amyloidosis. Results: Fifteen cases were identified, mostly amyloid A (AA) with multiple organ involvement. Only one case of pulmonary amyloidosis was reported. To date, no cases of pulmonary light-chain amyloidosis (AL) have been described in CVID patients without an underlying plasma cell dyscrasia. Our patient initially presented with AA amyloidosis but evolved to systemic AL type with rapid progression and fatal outcome despite therapy. Conclusions: Amyloidosis should be considered in CVID patients with atypical symptoms. Accurate amyloid typing is essential as treatment differs between AA and AL types. Early recognition may improve outcomes.

Patients with systemic lupus erythematosus (SLE) are predisposed to Epstein-Barr virus (EBV) reactivation and the subsequent development of lymphoproliferative disorders (LPDs) due to immune dysregulation and prolonged immunosuppressive therapy. We report a case of a 42-year-old woman with a 26-year history of SLE who had been clinically stable for several years on low-dose prednisolone, azathioprine, cyclosporine, and hydroxychloroquine. She presented for evaluation of persistent fevers and abdominal pain. Imaging studies revealed segmental small bowel thickening with mesenteric hyperemia, suggestive of lupus enteritis. Laboratory findings included hypoalbuminemia and elevated inflammatory markers, but no serologic evidence of active lupus. Histologic examination of small intestinal biopsies revealed a polymorphic lymphoid infiltrate with atypical B cells positive for EBV, leading to a diagnosis of EBV-associated LPD. Following a reduction in immunosuppressive therapy and initiation of rituximab, the patient achieved clinical and radiologic improvement. This case highlights the importance of considering EBV-LPD in the differential diagnosis of gastrointestinal manifestations in SLE patients, particularly when serologic markers of active lupus are absent. The overlapping clinical and imaging features of lupus enteritis and EBV-LPD can lead to diagnostic delays, making histopathologic assessment crucial for accurate identification. The case also underscores the potential risk of EBV-LPD associated with long-term immunosuppressive treatment in SLE. Careful monitoring for lymphoproliferative complications is warranted in patients undergoing sustained immunosuppression.

Introduction Elevated inflammation and immune dysregulation are the main consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The dysregulated inflammatory state persists after coronavirus disease 2019 (COVID-19), establishing the post-acute sequelae of SARS-CoV-2 infection in individuals with long COVID (LC). The role of CD169 + monocytes in the early diagnosis of SARS-CoV-2 infection and their association with severe outcomes were demonstrated in COVID-19 patients (COV). We aimed to delineate specific myeloid activation that characterizes the acute and post-acute phases of SARS-CoV-2 infection, evaluating the correlation between cellular and extracellular vesicles (EVs). Methods Blood samples from COV, LC, and healthy donors (HD) were collected at Tor Vergata University Hospital in Rome. Plasmatic EVs were isolated by differential centrifugation and evaluated by flow cytometry and atomic force microscopy (AFM). Leukocyte subpopulations and different sizes of circulating EVs (100–200, 240–500, >500 nm) were characterized for HLA-DR and CD169 expression in COV, LC, and HD through flow cytometry. Serum inflammatory markers were assessed by the ELLA immunoassay system. The analyzed markers were associated with clinical and biochemical parameters in COV and LC. Results The analysis of HLA-DR + , CD169 + , and HLA-DR + CD169 + leukocytes confirmed our previous results in which the activated monocytes CD169 + HLA-DR + were found significantly high in COV, persisting in LC, and correlated differently with coagulation markers and inflammatory cytokines. Similar to cellular levels, the percentage and number of HLA-DR + CD169 + EVs were significantly elevated in COV and persisted in LC compared to HD. Different HLA-DR and CD169 expressions were found according to EV size in COV, LC, and HD, and correlations with biochemical parameters and circulating inflammatory markers were found. A positive correlation of HLA-DR and CD169 expression among monocytes and circulating EVs was found, supporting a possible connection between the two compartments and circulating inflammatory mediators. Moreover, the characterization by flow cytometry of EV cell derivation and cytokine cargo revealed EVs as sensitive indicators of both acute and persistent immune perturbations, bridging viral antigen persistence with inflammatory signaling in long COVID. Conclusion Myeloid activation markers and inflammatory cytokines are dynamically expressed between blood cells and circulating extracellular vesicles, underlining multilevel cell-to-cell communications, opening new possibilities to monitor COVID-19 and long COVID-associated sequelae.

In indolent small B-cell lymphomas, autoimmune cytopenia and histologic transformation pose important diagnostic and management challenges. MYD88 and MYC abnormalities are rarely reported in splenic marginal zone lymphoma (SMZL), and their role in immune dysregulation and transformation remains unclear. We describe a 44-year-old man with a small B-cell lymphoma highly suspicious for SMZL, who presented with severe warm autoimmune hemolytic anemia, massive splenomegaly, and lymphocytosis. He harbored both MYD88 L265P mutation and MYC copy-number gain within a complex karyotype, in the absence of splenic histology. This case, together with a review of the literature, suggests that such “clinically indolent but genetically high-risk” SMZL-like lymphomas may carry a non-negligible risk of progression and transformation and therefore require close longitudinal monitoring. Further accumulation of similar cases and molecular data is needed to clarify the prognostic and biological impact of MYD88 and MYC alterations in this setting.

Background Asthma is a chronic inflammatory airway disease characterized by airflow limitations, airway remodeling, and immune dysregulation. Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) has recently been implicated in inflammatory and remodeling processes in the body. However, its clinical significance and mechanistic role in asthma are unclear. This study aimed to investigate the association between soluble LYVE-1 (sLYVE-1) levels and asthma severity, airway inflammation, and remodeling, and to elucidate its regulatory role in airway smooth muscle cell (ASMC) activation via the PI3K/Akt signaling pathway. Methods A total of 238 participants were enrolled, including 80 healthy controls, 72 patients with asthma who were in remission, and 86 patients with acute asthma. Clinical characteristics, pulmonary function parameters, inflammatory and remodeling biomarkers, and serum sLYVE-1 levels were assessed. Correlation analyses were performed to evaluate the relationship between sLYVE-1 and disease-related parameters. Mechanistic studies were conducted in vitro using platelet-derived growth factor-BB (PDGF-BB)-stimulated ASMCs with LYVE-1 knockdown to explore the downstream signaling and functional effects. Results Serum sLYVE-1 levels were significantly elevated in patients with asthma and progressively increased with disease severity. sLYVE-1 levels were inversely correlated with forced expiratory volume in one second (FEV1) and FEV1/FVC and positively correlated with total immune globulin E (IgE), eosinophil counts, T-helper cell type 2 (Th2) and T-helper cell type 17 (Th17) cell proportions, fractional exhaled nitric oxide (FeNO), type 2 cytokines, and airway remodeling-associated mediators, including vascular endothelial growth factor A (VEGF-A), stromal-derived factor 1α (SDF-1α), transforming growth factor-β1 (TGF-β1), matrix metalloproteinases-9 (MMP-9), and hyaluronan (all p < 0.001). In vitro , LYVE-1 silencing markedly attenuated PDGF-BB-induced PI3K/Akt phosphorylation, ASMC proliferation and migration, extracellular matrix-related gene expression, and pro-inflammatory cytokine secretion while reducing oxidative stress and enhancing antioxidant activity. Conclusion Elevated circulating sLYVE-1 levels are closely associated with asthma severity, airway inflammation, and airway remodeling. Mechanistically, LYVE-1 promoted PDGF-BB-induced ASMC activation through PI3K/Akt signaling, highlighting LYVE-1 as a potential biomarker and potential therapeutic target for asthma.

Topical ionic liquid-mediated GLUT1 gene editing ameliorates psoriasis and prevents recurrence.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options and high relapse rates. Live bacterial therapeutics (LBTs) offer a promising alternative by restoring mucosal integrity, modulating immunity, and rebalancing gut microbiota; however, their clinical translation is constrained by poor storage stability, low gastrointestinal survivability, and limited therapeutic functionality. Here, we report a multilevel, modular encapsulation strategy that integrates a metal-polyphenol network (MPN) and silica-based shell with iron-based metal-organic framework (MIL-101(Fe)) nanocomponents to construct a biohybrid probiotic system (Bif@FCSM(A), where "A" denotes 5-aminosalicylic acid). This hierarchical assembly forms an oxygen-shielding, mechanically reinforced shell, resulting in a 41-fold improvement in aerobic storage stability and an 871-fold enhancement in gastric survivability of the anaerobe Bifidobacterium longum. Incorporation of MIL-101(Fe) enables high-capacity drug loading and inflammation-responsive disassembly via transferrin (Tf)-mediated Fe3 + chelation in inflamed colonic tissue, thereby achieving spatiotemporally controlled bacterial activation and drug release. Guided by UC transcriptomic signatures, this combinatorial design concurrently targets immune dysregulation and microbial imbalance. In a dextran sulfate sodium-induced murine UC model, Bif@FCSM(A) markedly alleviated disease severity, suppressed pro-inflammatory cytokines, restored mucosal immune homeostasis, and enriched short-chain fatty acid-producing taxa. This work establishes a programmable, pathology-responsive probiotic platform with translational potential for complex inflammatory diseases.

Hepatitis B virus reactivation (HBVr) poses a serious clinical challenge and potentially life-threatening complication in patients with hepatocellular carcinoma (HCC), particularly amid the expanding use of modern immunotherapeutic agents. Despite progress in antiviral prophylaxis and refined risk-stratification strategies, HBVr continues to compromise treatment efficacy and survival outcomes, especially in patients receiving immune checkpoint inhibitors, tyrosine kinase inhibitors, or combination regimens. This review comprehensively synthesizes current evidence on the virological foundations, clinical risk factors, and immunopathological mechanisms underpinning HBVr during HCC treatment, emphasizing the pivotal roles of covalently closed circular DNA (cccDNA) persistence and treatment-induced immune dysregulation. We further examine the comprehensive evidence of risk factors in HBVr, including various treatments for HCC. We also reviewed the clinical consequences of HBVr, including acute hepatocellular injury, unplanned treatment discontinuations, and adverse long-term HCC prognosis. Evidence-based management approaches, such as universal serological screening, individualized antiviral prophylaxis, and multidisciplinary coordination, are detailed to effectively reduce reactivation risk. Finally, we discuss emerging therapeutic strategies, including HBV-specific cellular therapies and innovative siRNA-based and immunostimulatory cytokine delivery platforms, which offer promising avenues for eradicating viral reservoirs and restoring immune surveillance.

Immunopathology of Immune Thrombocytopenia.

Spinal cord injury (SCI) causes permanent neurological deficits, and immune responses play a pivotal role in tissue regeneration and functional recovery. Dendritic cell (DC) vaccines have shown considerable potential for modulating injury-induced immune dysregulation. However, their therapeutic efficacy is limited by factors such as restricted cellular viability, delayed onset of action, and lack of sustained immune activity. Therefore, to address these challenges, a hybrid hydrogel composed of a methacrylate-modified decellularized lymph node extracellular matrix (DLMMA) and porous GelMA (pGelMA) carrying a neuroprotective DC (npDC) vaccine was developed in the form of cryomicroneedles (pG/DL@npDC-cryoMNs), enabling efficient and sustained immunological regulation during SCI treatment. The pG/DL@npDC-cryoMNs enhanced the viability of npDC vaccine and facilitated rapid npDC release, thereby inducing neuroprotective immunity at the injury site during the early stage. In addition, pG/DL@npDC-cryoMNs fostered the formation of a non-typical artificial tertiary lymphoid structure (naTLS) that lacked the complete organized structure of typical TLS yet effectively recruited and engaged immune cells to promote SCI repair. Moreover, pG/DL@npDC-cryoMNs maintained immunomodulatory activity for up to two weeks, facilitating neuronal regeneration in a mouse model of SCI. Overall, these findings highlight the therapeutic potential of pG/DL@npDC-cryoMNs in promoting SCI repair by establishing a neuroprotective immune microenvironment.

Thunderstorm asthma (TA) refers to a phenomenon characterized by sudden onset, large-scale outbreaks, and potentially fatal acute exacerbations of asthma. Despite accumulating epidemiological evidence, its cellular and molecular mechanisms remain unclear. Recent studies have proposed a core framework involving "environmental triggers-epithelial barrier damage-immune dysregulation." During thunderstorms, high humidity and strong convection can cause pollen to hydrate and rupture into sub-pollen particles (SPPs) smaller than 2.5μm, which may further combine with other pollutants such asparticulate matter ≤ 2.5μm(PM2.5) and ozone (O3) to form bioaerosols capable of penetrating small airways. These factors can lead to damage of the airway epithelial barrier, with sequential cellular and molecular pathophysiological changes including downregulation of various tight junction proteins in the epithelial barrier, imbalance of mucociliary clearance function, and upregulated secretion of epithelial alarmins such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). This results in increased disease severity through activation of innate and adaptive immunity (e.g., type 2 innate lymphoid cells (ILC2)/T helper 2(Th2) axis activation leading to immunoglobulin E(IgE) upregulation, eosinophil activation, and mast cell degranulation; Th17-mediated neutrophilic inflammation; and toll-like receptor(TLR)-mediated innate immune processes and mucosal inflammation) and enhancement of intrinsic susceptibility factors (e.g., TLR gene polymorphisms and abnormal expression, DNA methylation and histone modifications, as well as microbiome-host interactions). According to research in meteorology, exposomics, and molecular immunology, we believe that airway epithelial barrier dysfunction and immune dysregulation play significant roles in TA. Future translational directions primarily involve establishing a population stratification and early warning system through combinations of meteorological factors with allergens/pollutants, thereby enhancing public protection and health management efforts to improve the early warning, prevention, and clinical management of TA.

Gastric ulcer (GU) remains a significant global health concern, often leading to severe complications such as bleeding and perforation. While Helicobacter pylori infection and nonsteroidal anti-inflammatory drug use are well-recognized etiological factors, systemic inflammation plays a pivotal but underexplored role in GU pathogenesis. Shen et al provide compelling evidence linking complete blood count-derived inflammatory biomarkers with GU prevalence, identifying the systemic inflammatory response index as the most discriminative marker. Their cross-sectional analysis underscores the potential of routine hematological parameters as cost-effective, accessible tools for early identification of high-risk individuals. Importantly, this study adds to the growing body of literature suggesting that simple indices - neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and systemic inflammatory response index - may serve not only as diagnostic aids but also as windows into disease mechanisms involving immune dysregulation and oxidative stress. Future prospective and mechanistic studies are warranted to determine whether these markers can predict ulcer recurrence, guide therapeutic interventions, or integrate into precision gastroenterology. By leveraging widely available blood tests, we may move closer to a paradigm where inexpensive inflammatory indices refine GU risk stratification and management strategies.

There has been tremendous progress in the understanding of subsets of regulatory T cells (Tregs). However, despite their theoretical importance, Treg subsets are not routinely analyzed in patients with immune dysregulation over the course of the disease and treatment. This is particularly the case in pediatric patients when the primary patient material is limited. Here, we used a rapid permeabilization assay to analyze CD4 + CD25 hi FOXP3 + and CD4 + CD25 hi CD127 low Tregs with subsets including Helios + Treg, Helios − Treg, Helios + CD39 + Treg, CD62L + CD45RA + Treg, CD62L + CD45RA − Treg, and FOXP3 hi CD45RA − Treg in a predominantly pediatric cohort of patients with an inborn error of immunity (IEI) affecting their Treg compartment due to pathological variants in the lipopolysaccharide-responsive beige-like anchor protein (LRBA) gene. Longitudinal data were collected during abatacept treatment and after allogeneic hematopoietic stem cell transplantation (alloHSCT). Abatacept treatment led to a decrease in Helios − Treg (p = 0.049) over a 10-month treatment period and a significant increase in Helios + Treg (p = 0.024). This was accompanied by clinical amelioration of disease symptoms, which was captured accordingly using the immune deficiency and dysregulation activity (IDDA2.1) score.

Alopecia areata (AA) is a common, immune-mediated, non-scarring alopecia characterized by unpredictable hair loss and substantial psychosocial burden. Once considered a hair-restricted disorder, AA is now recognized as a systemic disease arising from complex interactions between genetic susceptibility, immune dysregulation, environmental triggers, intrinsic hair follicle vulnerabilities. Central to disease pathogenesis is the collapse of hair follicle, driven predominantly by cytotoxic CD8⁺NKG2D⁺ T cells within a Th1-skewed cytokine milieu dominated by interferon-γ and interleukin-15. Genome-wide association studies have identified multiple susceptibility loci, including HLA class II genes and immune regulatory pathways, while emerging evidence implicates hair-shaft–specific genes, oxidative stress regulators, and epigenetic modifiers, underscoring disease heterogeneity beyond classical autoimmunity. Environmental factors such as smoking, sleep disturbance, psychological stress, and microbiome dysbiosis, further modulate disease risk and severity. Advances in Trichoscopy have refined non-invasive diagnosis and disease monitoring, while therapeutic strategies have expanded from conventional corticosteroids to targeted Janus kinase inhibitors, representing a paradigm shift in disease management. However, challenges related to long-term safety, relapse, accessibility, and cost still remain. This review integrates current insights into AA pathogenesis, diagnostics, and emerging therapies, emphasizing the need for personalized, multidisciplinary, and translational approaches to improve long-term outcomes and quality of life.

Immune dysregulation plays a pivotal role in the pathophysiology of sepsis and COVID-19, with lymphopenia emerging as a consistent marker of severity and poor prognosis. However, most existing studies have assessed lymphocyte counts at isolated time points, limiting insights into their temporal behavior and prognostic value. The dynamics of lymphocyte recovery or persistence of lymphopenia remain largely unexplored in large populations, as well as the impact of adjunctive therapies such as corticosteroids. We hypothesized that the persistence or recovery of lymphopenia may be key to understanding disease progression and predicting outcomes. Using the multinational ISARIC cohort, we investigated longitudinal lymphocyte trajectories in hospitalized patients and the clinical determinants associated with their evolution over time. We conducted a multinational prospective observational cohort study using data from the ISARIC-WHO Clinical Characterization Protocol. Patients with confirmed SARS-CoV-2 infection and at least four lymphocyte measurements during the first 28days of hospitalization were included. We analyzed lymphocyte trajectories, Cox regression survival analyses and multivariable linear regression modelling. We also applied multistate models and joint modeling to assess the association between lymphocyte trajectories and 28-day mortality, incorporating corticosteroid use as a time-varying covariate. Of 945,317 screened patients, 231,933 hospitalized adults with confirmed COVID-19 and sufficient lymphocyte data were included, with 56.6% classified as lymphopenic. Lymphopenia was independently associated with higher rates of ICU admission, organ support, and in-hospital mortality (OR = 1.52, 95% CI 1.48-1.55), and lower absolute lymphocyte counts were strongly linked to worse survival in adjusted Cox models (HR = 1.33 per 1 × 10⁹ cells/L decrease, 95% CI 1.28-1.38). Multistate modeling revealed that lymphopenic patients had a significantly higher daily transition rate to death and a shorter duration in that immune state, while corticosteroid exposure was associated with an increased likelihood of entering and remaining in lymphopenia. Joint modeling identified age, sex, and corticosteroid use as significant predictors of lower lymphocyte trajectories over time, with distinct dynamics between survivors and non-survivors. Lymphopenia was common and strongly associated with worse outcomes in hospitalized COVID-19 patients, with impaired recovery particularly evident in those receiving corticosteroids. These findings highlight the value of lymphocyte monitoring to inform tailored immunomodulatory strategies in sepsis and severe viral infections.