Frontiers in Immunology最新文献

Background: Ménière's disease (MD) is a complex disorder whose pathogenesis extends beyond endolymphatic hydrops to involve dysregulated immune responses. While a subset of patients exhibits a "low-cytokine phenotype" during remission, the mechanisms underlying the transition to acute inflammatory attacks triggered by environmental factors remain poorly understood.

Methods: We employed an integrative multi-omics approach to explore the immune microenvironment of MD. This included bioinformatic analysis of differentially expressed genes (DEGs) from GSE109558, featuring PBMCs from MD patients and healthy controls stimulated with Aspergillus or Penicillium. Protein-protein interaction (PPI) networks, immune infiltration analysis, and single-cell RNA sequencing (GSE269117) were utilized to identify hub genes and cellular interactions. Key findings were validated in an independent cohort through measurement of serum cytokines, in vitro macrophage stimulation assays, and immunofluorescence staining.

Results: Bioinformatic analysis revealed a latent hyperinflammatory potential in MD PBMCs, which was unmasked upon fungal challenge, showing significant enrichment in neutrophil chemotaxis and NF-κB pathways. We identified 20 hub genes, with CXCL8 emerging as a top candidate. Single-cell sequencing and CellChat analysis pinpointed macrophages as the dominant source of CXCL8 and key orchestrators of intercellular communication, notably via the ALCAM-CD6 pathway with T cells. In vitro verification confirmed this macrophage-driven inflammatory cascade response. Under the stimulation of LPS/β -glucan, the level of CXCL8 secreted by macrophages in MD patients increased (p < 0.01), while there was no difference before and after stimulation in the healthy control group. Serum levels of CXCL8, IL-6, and IL-17A were also significantly elevated in MD patients during attacks.

Conclusion: Our findings support a novel "hypoimmune-hyperinflammatory switch" model in MD, wherein macrophages play an important role in initiating and amplifying inflammatory responses to environmental triggers via CXCL8 production and cellular crosstalk. This refined understanding of the immune axis in MD provides a foundational basis for developing targeted immunomodulatory therapies.

Background: Atlantic cod lack functional MHC class II and CD4, raising fundamental questions about how vaccination generates protection in this species.

Methods: We combined single-cell transcriptomic profiling of splenic cells with qRT-PCR across complementary active vaccination and passive serum-transfer experiments to define cellular and transcriptional correlates of immunity to Vibrio anguillarum.

Results: Bath-vaccinated fish and recipients of immune serum showed effective containment of infection, with bacterial signals largely restricted to gills and minimal detection in spleen or head kidney, whereas naïve fish frequently developed high systemic bacterial loads by day 3 post-infection. All groups exhibited increased splenic macrophage abundance following challenge, but only naïve fish showed strong and sustained inflammatory activation, consistent with their higher pathogen burden. Vaccinated fish and immune-serum recipients displayed only transient or weak myeloid responses despite similar early neutrophil activation. Across both experimental models, a transcriptionally distinct B-cell subset expanded at the peak of infection. This population showed increased immunoglobulin and MHC class I expression together with innate sensing features, consistent with an activated B-cell state. Although this B-cell subset increased in all groups, the largest expansions were observed in vaccinated fish and immune-serum recipients. Overall, these findings are consistent with antigen-specific IgM enhancing early B-cell activation and contributing to protection against V. anguillarum through coordinated humoral and innate-like B-cell responses.

Discussion: These findings identify an antibody-driven mode of immune coordination that operates independently of classical CD4⁺ T-cell help and provide insight into how effective vaccination can be achieved in vertebrates with divergent adaptive immune architectures.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, linked to greater risk of heart failure, stroke and death. Inflammation has been connected to AF emergence, however mechanisms of inflammation-caused AF remain thus far elusive, leading to a lack of mechanism-based treatments. An isogenic, 3D tissue model containing hiPSC-derived atrial-like cardiomyocytes (aCM), cardiac fibroblasts (cfb), and cardiac macrophages was engineered using custom injection-molded pillar devices. Electrophysiological changes were examined via sharp electrode recordings, calcium imaging, and multi-electrode assays. Gene function was interrogated using siRNA knock-down, lentiviral overexpression, and pharmacological modulation. In silico tissue and whole-heart models validated findings under simulated stress and heterogeneous conditions. Activation of M1 macrophages led to a 50% reduction in contraction amplitude, action potential spike amplitude (aCM+cfb+M1: 61.3 mV ±13.9 vs control: 71.6 mV ±14.5, p < 0.01) and increased beat irregularity (M1: 150.7% ± 388.9 vs control, p < 0.001). Calcium transient amplitude was reduced (12.3 a.u. ± 14.7, p < 0.05) and upstroke velocity slowed. SCN5A knock-down reduced contraction amplitude (-51.9% ± 37.2, p < 0.01) without inducing arrhythmias, whereas combined GJA5 and ATP1A1 knock-down induced significant irregularity (403% ± 371.3, p < 0.001), increased conduction heterogeneity (+18%), and reduced velocity (-52.4%). In silico modeling confirmed that paired 50% downregulation of sodium-potassium pump and tissue conductivity induced AF under tachycardia even without ectopic activity. This work reveals a novel, inflammation-driven mechanism for AF initiation. Combined downregulation of GJA5 (connexin 40) and ATP1A1 (NaK ATPase) disrupted intercellular connectivity and ion flux, establishing a substrate for arrhythmogenesis. These results were robust across in vitro, genetic/pharmacological, and in silico models, defining new avenues for translational intervention.

Introduction: Metastatic recurrence drives dismal survival in esophageal squamous cell carcinoma (ESCC), yet epigenetic mechanisms underlying metastasis remain poorly defined. While DNMT1 and DNMT3A contribute to ESCC pathogenesis, DNMT3B's role is enigmatic despite frequent dysregulation.

Methods: Integrated methylome-transcriptome profiling comprised genome-wide methylation screening in 5 paired ESCC tumor and adjacent normal tissues. Parallel mRNA microarray profiling quantified expression levels of DNMT3B, CADM2, and ADAMTS9-AS2 in ESCC tumors. RIP, ChIP, and pyrosequencing in ESCC cells validated molecular interactions.

Results: ADAMTS9-AS2 downregulation promoted ESCC proliferation, migration, and invasion. Mechanistically, ADAMTS9-AS2 directly bound DNMT3B, preventing its occupancy at the CADM2. Rescue experiments confirmed CADM2 overexpression reversed ADAMTS9-AS2 knockdown-induced oncogenic phenotypes. Clinically, DNMT3B overexpression in lymph node-positive tumors correlated with metastatic progression.

Discussion: ADAMTS9-AS2 functions as an epigenetic brake by sequestering DNMT3B, thereby blocking CADM2 epigenetic silencing and metastasis in ESCC. Targeting this axis offers potential therapeutic strategies against ESCC.

The immunometabolic checkpoint axis formed by the IDO1/AhR pathway and the HIF-1α pathway, which functionally antagonize each other via their competition for the shared transcriptional partner aryl hydrocarbon receptor nuclear translocator (ARNT), profoundly regulates the pathogenesis and progression of autoimmune diseases. Following activation of the aryl hydrocarbon receptor (AhR) by kynurenine (Kyn), a tryptophan metabolite generated by IDO1, the activated AhR and hypoxia-induced HIF-1α intensely compete for the limited pool of ARNT protein. This competition results in the formation of two distinct transcriptional complexes: AhR/ARNT and HIF-1α/ARNT. These complexes drive opposing immune programs. The AhR/ARNT complex promotes immune tolerance by facilitating Treg cell differentiation, inducing a tolerogenic phenotype in dendritic cells, promoting M2 macrophage polarization, and sustaining the survival of long-lived plasma cells. Conversely, the HIF-1α/ARNT complex enhances glycolysis and amplifies inflammation, driving Th17 cell differentiation, activating the pro-inflammatory functions of dendritic cells, promoting M1 macrophage polarization, and stimulating plasmablast proliferation. In autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and membranous nephropathy (MN), dysregulation of this axis is characterized by excessive HIF-1α signaling and relative insufficiency of the IDO1/AhR pathway. This imbalance leads to the monopolization of ARNT by the HIF-1α pathways, consequently exacerbating Treg/Th17 imbalance, autoantibody production, and tissue damage. Targeting this axis, for instance through combined HIF-1α inhibitors and IDO1/AhR pathway agonists, holds promise as a novel metabolic intervention strategy for autoimmune diseases.

Severe asthma remains a major unmet clinical challenge, largely due to corticosteroid hyporesponsiveness in a subset of patients. Despite high-dose inhaled or systemic corticosteroids and targeted biologics, chronic airway inflammation often persists, particularly in T helper 2 (Th2)-low, neutrophilic, and mixed inflammatory phenotypes. Corticosteroid failure in severe asthma reflects not only excessive inflammation but a fundamental breakdown of immune regulatory mechanisms. At the molecular level, steroid hyporesponsiveness is associated with impaired glucocorticoid receptor (GR) signaling, including an altered GRα/GRβ balance, sustained activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways, oxidative stress-mediated histone deacetylase 2 (HDAC2) dysfunction, and epigenetic stabilization of pro-inflammatory transcription. Concurrently, regulatory immune networks-particularly regulatory T and B cells that normally enforce immune tolerance and promote inflammatory resolution-are quantitatively and functionally compromised. Although biologics targeting immunoglobulin E (IgE), interleukin-5 (IL-5)/IL-5 receptor alpha (IL-5Rα), and IL-4 receptor alpha (IL-4Rα) have improved type-2-high asthma, their efficacy in steroid-hyporesponsive disease remains limited, as they do not restore immune regulation or glucocorticoid sensitivity. In this context, IL-35 has emerged as a uniquely positioned immunoregulatory cytokine. Produced mainly by regulatory T and B cells, IL-35 suppresses Th17-driven and innate immune inflammation, inhibits MAPK and NF-κB signaling, expands regulatory immune networks through infectious tolerance, and stabilizes epithelial barrier integrity. Importantly, IL-35 restores corticosteroid sensitivity in experimental models by targeting key drivers of steroid resistance. This review highlights IL-35 as a potential therapeutic target for managing steroid-hyporesponsive severe asthma by linking asthma endotypes, steroid resistance mechanisms, and IL-35 biology.

Background: Tuberculosis (TB) remains a leading opportunistic infection in immunocompromised hosts. Disruption of host-pathogen interactions under cumulative immunosuppression may result in atypical extrapulmonary disease with indolent clinical manifestations and tumor-mimicking radiologic features, leading to substantial diagnostic delay.

Case presentation: A 67-year-old man with Crohn's disease on cumulative immunosuppressive therapy, including biologics and a Janus kinase inhibitor, developed progressive mediastinal lymphadenopathy and a paravertebral mass with associated vertebral destruction on chest computed tomography, despite prior completion of isoniazid prophylaxis for latent TB infection. The aggressive, tumor-like imaging appearance raised a strong suspicion of metastatic malignancy. Conventional endobronchial ultrasound-guided transbronchial needle aspiration was nondiagnostic. As a salvage diagnostic approach, endobronchial ultrasound-guided tunneling biopsy obtained histological core tissue from a subcarinal lymph node. Although histopathology showed nonspecific fibrous changes without identifiable acid-fast bacilli, Xpert MTB/RIF testing detected Mycobacterium TB complex DNA at trace levels. A diagnosis of mediastinal tuberculous lymphadenitis complicated by a paravertebral cold abscess and secondary vertebral osteomyelitis was ultimately established. The patient subsequently showed marked radiological improvement with standard anti-TB therapy.

Conclusion: This case illustrates how cumulative immunosuppression can profoundly alter host immune responses to Mycobacterium TB, resulting in tumor-like extrapulmonary disease and diagnostic ambiguity. Integration of advanced tissue acquisition with molecular testing may be essential for diagnosing TB when disrupted host-pathogen interactions limit conventional diagnostic yield.

[This corrects the article DOI: 10.3389/fimmu.2026.1682589.].