Search Results (197)

Background: Neutrophils play a role in idiopathic inflammatory myopathies (IIMs), especially in vasculopathic manifestations. While neutrophil extracellular traps (NETs) and low-density granulocytes (LDGs) have been described, the functional relevance of other subsets—such as naïve neutrophils, reverse transendothelial migration neutrophils (rTEM), myeloid-derived suppressor cells (MDSCs), and regulatory neutrophils—and their association with vasculopathy remains unknown. Objective: We aimed to characterize the phenotypic and functional profile of neutrophil subsets and their association with vasculopathic manifestations in IIM, adjusting for disease activity. Methods: We conducted a cross-sectional, single-center study including 59 IIM patients diagnosed by muscle biopsy and fulfilling 2017 ACR/EULAR criteria. Flow cytometry was used to immunophenotype myeloid subsets, and functional assays assessed phagocytosis and respiratory burst. Patients were stratified by clinical activity and presence of vasculopathy. Results: Vasculopathic patients showed expansion of LDGs (p = 0.0092), granulocytic and monocytic MDSCs expressing Arginase-1 (p = 0.0078, p = 0.0003) and PD-L1 (p = 0.0258, p = 0.0087), and rTEM neutrophils (p = 0.0775). In contrast, they exhibited a reduction in naïve neutrophils (p = 0.0004), phagocytosis (p < 0.0001) and respiratory burst (p = 0.0006). Multivariate analysis identified naïve neutrophils and activated CD177⁺ neutrophils as independent predictors of vasculopathy. A positive correlation between activated and naïve neutrophils were observed in patients with vasculopathic features (r = 0.43; p < 0.05). Conclusions: IIM patients with vasculopathic features display a distinct immune profile characterized by an imbalance between proinflammatory and regulatory neutrophil subsets, alongside persistent functional impairment. Full article

Background/Objectives: Reactive oxygen species (ROS) are key effectors of innate immunity but can also contribute to inflammation and tissue injury when their production is dysregulated. Although antibiotics are primarily selected for their antimicrobial activity, prolonged treatment may also influence host immune responses. However, the effects of anti-tuberculosis drugs on ROS production across innate immune cell subsets have not been assessed, especially not for novel drugs currently used against multi drug-resistant (MDR) tuberculosis (TB). Methods: Whole blood from healthy donors was incubated with seven antimycobacterial drugs used against MDR TB at sub-therapeutic, therapeutic, and supra-therapeutic concentrations. ROS production was quantified by flow cytometry using dihydrorhodamine 123 (DHR-123) in neutrophils, classical monocytes, and eosinophils under unstimulated conditions or following stimulation with Escherichia coli, fMLP, or PMA. Results: Bedaquiline and clofazimine decreased ROS production in neutrophils and classical monocytes across multiple stimuli (median values of Rh-123⁺ classical monocytes after E. coli stimulation without BDQ was 30.8% versus 24.9% with 1 µg/mL BDQ (p < 0.05, therapeutic concentration) and 31.3% without CFZ versus 19.2% with 1 µg/mL CFZ (p < 0.01, therapeutic concentration) in the same conditions). In contrast, levofloxacin and linezolid showed no detectable impact on ROS production in any cell population. Pretomanid uniquely induced a reduction in ROS generation in eosinophils and classical monocytes while sparing neutrophil oxidative burst activity, distinguishing it from other antibiotics tested (34.1% decrease in Rh-123 MFI of eosinophils between the control and PA 3 µg/mL after fMLP stimulation, p < 0.01, therapeutic concentration). Conclusions: These findings demonstrate that first line drugs against MDR TB display heterogeneous and cell type-specific effects on innate immune oxidative responses. Such differential effects on host immunity may have implications for both antimicrobial efficacy and inflammation control during tuberculosis treatment. Full article

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease, with macrophages playing a critical role in its pathological remodeling. Our study aims to investigate the molecular basis of HCM by analyzing macrophage-related gene expression at the single-cell level. Utilizing published scRNA-seq datasets (GSE181764 and GSE161921), we identified macrophages as the key cell cluster most associated with HCM. Integration with bulk RNA-seq data (GSE249925) and differential expression analysis revealed three hub genes: ASPN (asporin), F13A1 (Coagulation Factor XIII A Chain), and SORBS2 (Sorbin and SH3 domain-containing protein 2). Immune infiltration analysis showed significant decreases in multiple immune cell subsets in HCM patients, including neutrophil and macrophages. Intercellular communication analysis revealed an approximately 50% reduction in total interactions in HCM, accompanied by markedly weakened macrophage signaling reception and loss of regulatory pathways. Single-cell validation confirmed that F13A1 expression was predominantly restricted to macrophage clusters and significantly downregulated in HCM macrophages, demonstrating strong macrophage specificity and diagnostic potential. Furthermore, a LASSO-based diagnostic model incorporating three genes (IGFBP4, FOS, CTSC) exhibited high predictive performance, with validated accuracy in both training and external validation sets. Collectively, our findings shed light on the mechanisms underlying macrophage dysfunction in HCM and offer novel insights into the cellular and molecular dynamics. Full article

Background: The immune mechanism of diabetic kidney disease (DKD) has not yet been fully elucidated. This study aimed to characterize circulating lymphocyte subsets in patients with type 2 diabetes mellitus (T2DM), with a particular focus on DKD-related immune alterations and prognosis. Methods: Circulating T cells, B cells and NK cells were identified by flow cytometry. The primary endpoint was all-cause mortality, and overall survival was defined as the time from enrollment to death from any cause or last follow-up. Associations between lymphocyte subsets, inflammatory indices and renal function parameters were analyzed. Cox regression was used to identify factors associated with overall survival in patients with DKD and in the whole T2DM cohort. A prognostic nomogram was developed in the whole T2DM cohort to estimate 1-, 2-, 3-, and 5-year overall survival (OS) probabilities. Model performance was evaluated using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Mendelian randomization (MR) was performed as a further exploratory analysis to assess whether immune-related traits were genetically associated with DKD susceptibility, with inverse variance weighting (IVW) as the primary analytical method. Results: In total, 74 T2DM patients were divided into DKD (stage 3–4 of chronic kidney disease) and non-DKD groups. Median follow-up duration was 34.6 months. DKD patients exhibited elevated levels of NK cells, the monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). In patients with DKD, higher PLR and serum creatinine (SCr) were associated with poorer overall survival, whereas CD4⁺CD25⁺ T cell frequency was not significant after adjustment. In the whole T2DM cohort, higher frequency of circulating CD4⁺CD25⁺ T cells were associated with improved survival (HR 0.920, 95% CI 0.858–0.986, p = 0.019), whereas elevated PLR and SCr were linked to poorer outcomes. The exploratory nomogram incorporating CD4⁺CD25⁺ T cells, PLR, and SCr, showed acceptable internal performance in this cohort. As a separate exploratory analysis, MR suggested that genetically proxied CD4 expression on activated CD4 regulatory T cells was associated with a lower risk of DKD. Conclusions: DKD was associated with higher mortality and elevated MLR-, NLR-, PLR-, and NK cell levels in patients with T2DM. In patients with DKD, PLR and SCr were associated with overall survival, supporting the prognostic relevance of systemic inflammation and renal dysfunction. Individual lymphocyte subsets were not independently associated with survival in the DKD cohort after adjustment, whereas CD4⁺CD25⁺ T cell frequency provided additional prognostic information in the whole extended T2DM cohort analysis. Further validation is warranted. Full article

Background/Objectives: Vaginal cuff hematoma is a recognized complication following hysterectomy, with a subset of patients requiring invasive intervention. No reliable bedside biomarker currently exists to identify at admission patients likely to fail conservative management. This study aimed to evaluate the incidence and clinical characteristics of symptomatic vaginal cuff hematoma across all hysterectomy approaches, and to assess the predictive performance of the CALLY index (CRP-albumin-lymphocyte index), a composite marker of inflammatory burden, immune function, and nutritional status, alongside the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) for identifying patients requiring interventional management. Methods: This retrospective cohort study included 61 patients with symptomatic vaginal cuff hematoma following hysterectomy in a major tertiary referral center (November 2022–July 2025). Patients were divided into conservative (n = 38) and interventional (n = 23) management groups. The CALLY index was calculated as [Albumin (g/dL) × Lymphocyte (×10⁹/L)] ÷ [CRP (mg/L) × 10⁻²]. Receiver operating characteristic (ROC) curve analysis with the DeLong method was used to compare predictive performance. Results: The overall incidence of symptomatic vaginal cuff hematoma was 1.9% (73/3852 hysterectomies), with the highest rate following vaginal hysterectomy (3.32%) and the lowest after robotic hysterectomy (0.74%). Interventional management was required in 37.7% of patients. The interventional group had significantly higher CRP (192 vs. 62 mg/L, p < 0.001), NLR (7.53 vs. 4.17, p < 0.001), and SII (2308 vs. 1207, p < 0.001), and significantly lower CALLY index values (2.00 vs. 9.80, p < 0.001). The CALLY index demonstrated the highest predictive performance (AUC = 0.863, 95% CI: 0.762–0.964), outperforming SII (AUC = 0.801), NLR (AUC = 0.789), and PLR (AUC = 0.654). At the optimal cutoff of ≤2.89, the CALLY index yielded a sensitivity of 65.2% and a specificity of 92.1%. Conclusions: The CALLY index is a simple, routinely available composite biomarker that may help identify patients at higher risk for interventional management in symptomatic vaginal cuff hematoma. Its incorporation into postoperative assessment may improve risk stratification and support timely clinical decision-making. Full article

This study is a narrative review of natural killer (NK) cells in Behcet disease (BD). BD is an inflammatory disorder with manifestations in mucosal tissues. Unlike autoimmune diseases that generate autoantibodies, BD is believed to be an autoinflammatory disease triggered by innate immune cells rather than adaptive cells. Hyperactivation of neutrophils causes vasculitis and thrombosis, and they migrate into cutaneous and ocular lesions. Dominance of M1 macrophages promotes the differentiation of Th1 cells. Moreover, the cross-reaction of bacterial heat shock proteins induces production of cytokines such as IL-4 and IFN-γ in γδT cells, which alters the balance between Th1 and Th2 phenotypes. Nevertheless, NK cells play more critical roles in BD pathogenesis than other innate immune cells because not only is their activity precisely controlled by the interaction between ligands and receptors, but NK1 shift also elicits Th1 dominance. The genetic factors associated with BD are HLA-B51 and major histocompatibility complex class I-related chain A (MICA), which stimulate NK receptors as ligands. Improperly processed peptides dysregulate their interaction with NK receptors, triggering the inflammatory response. NK1 and NK2 subsets represent cytokine production in relapse and remission periods; however, the cytotoxicity of NK cells in relapse is lower than that in remission periods. It still remains unclear how NK cells are activated recurrently and expand cytokine production. This review highlights the regulation of gene expression encoding NK receptors, tissue-resident NK cells, and adaptive NK cells to discuss their potential for relapse. Splicing variants and readthrough genes encoding NK receptors easily alter cytokine production. Moreover, tissue-resident NK cells in mucosal tissues and adaptive NK cells that memorize the virus infection have the potential to trigger hyperactivation in relapse. Full article

Most infectious pathogens enter the host through mucosal surfaces, yet conventional injectable vaccines primarily induce systemic immunity without eliciting robust secretory immunoglobulin A (SIgA) responses at mucosal sites. The COVID-19 pandemic highlighted this limitation, as intramuscular mRNA vaccines failed to establish durable mucosal immunity in the upper respiratory tract. This review covers recent progress in mucosal vaccine development. We first discuss the organization of the mucosal immune system, focusing on SIgA induction, tissue-resident memory T (${\mathrm{T}}_{\mathrm{RM}}$) cells, and resident memory B (${\mathrm{B}}_{\mathrm{RM}}$) cells. We then examine mucosal adjuvants, from cholera toxin and heat-labile enterotoxin derivatives to stimulator of interferon gene (STING) agonists and a strategy to enhance alum adjuvanticity through neutrophil elastase inhibition. Delivery routes including intranasal, oral, and sublingual administration are reviewed alongside viral vectors, nanoparticles, mRNA-lipid nanoparticles, virus-like particles, and engineered bacterial platforms. The roles of innate immune cells, T helper cell subsets, and the microbiota in shaping vaccine responses are discussed. Finally, we survey licensed mucosal vaccines and the COVID-19 mucosal vaccine pipeline, analyze persistent barriers to clinical translation including the absence of validated mucosal correlates of protection, and outline future directions for thermostable formulations and systems biology-driven vaccine design. Full article

Aberrant pathogenic immune responses drive autoimmune uveitides; however, comprehensive leukocyte profiling in the conditions remains limited. Here, this exploratory pilot study aimed to elucidate the immunodynamics of ocular sarcoidosis (OS) and Vogt–Koyanagi–Harada disease (VKH) to identify blood diagnostic biomarkers during their acute phases. We performed a prospective observational analysis of ten newly diagnosed, treatment-naïve OS patients and seven VKH patients during their acute phases, along with eight healthy controls (HCs). Mass cytometry was utilized to quantify the proportions of 37 distinct leukocyte subsets. In OS group, the proportion of CD8⁺ naive was lower than in both VKH and control groups. Furthermore, the proportions of CD8⁺ central memory and γδ T cells were decreased compared to HC group. Hierarchical cluster analysis categorized the leukocyte subsets into four principal clusters: Cluster A (Th17-like, monocytes, neutrophils, etc.), Cluster B (Tregs, B cells, NK cells, basophils, etc.), Cluster C (CD8⁺ T cells, Th1-like, Th2-like, DCs, etc.), and Cluster D (CD4⁺ terminal effector, CD8⁺ terminal effector, and CD66b⁻ neutrophils). Compared to HC group, the abundance of Cluster A was relatively high in OS group, and the abundance of cluster B was relatively high in VKH group. In OS group, the proportions of CD8⁺ T cells and CD8⁺ terminal effector correlated negatively with serum ACE and sIL-2R levels. ROC curve analysis estimated that CD4⁺/CD8⁺ ratio (cut-off value: ≥3.46), the proportion of monocytes (≥9.41%), and the decreased proportions of CD3⁺ T cells (≤43.9%) and CD8⁺ T cells (≤10.0%) in peripheral blood may serve as potential blood biomarkers for diagnosing OS. The exploratory pilot study provides a comprehensive and simultaneous data of leukocyte subset proportions in the acute phase of OS and VKH, and our preliminary findings suggest that the proportions of specific leukocyte subsets may represent potential candidates for blood-based biomarkers in the diagnosis of OS. Full article

Interleukin-5 (IL-5) has long been positioned as a lineage-restricted cytokine primarily responsible for eosinophil differentiation and survival. However, emerging mechanistic and clinical evidence supports a broader conceptual shift: IL-5 should no longer be viewed solely as an eosinophil growth factor, but as a context-dependent regulator embedded within dynamic airway immune networks. Drawing on advances in eosinophil subset biology, receptor signaling, and tissue-level immune crosstalk, this review reframes IL-5 biology through the lens of systems-level inflammatory regulation across airway and systemic eosinophilic diseases. Recent data reveal functional heterogeneity between resident and inflammatory eosinophil subsets, challenging the assumption that blood eosinophilia uniformly reflects pathogenic activity. In parallel, functional IL-5 receptor expression has been identified on multiple structural and immune cell populations—including epithelial cells, mast cells, plasma cells, basophils, neutrophils, and fibroblasts—supporting a broader tissue-signaling paradigm. Experimental and translational studies further link IL-5 to epithelial integrity, airway remodeling, and mucus pathology, suggesting structural and network-level effects beyond simple eosinophil depletion. Comparative analyses across asthma, chronic rhinosinusitis with nasal polyps, and COPD demonstrate that eosinophilic inflammation is biologically heterogeneous and context-dependent. While IL-5-targeted therapies yield consistent benefit in severe asthma, therapeutic responses in other airway diseases appear to be shaped by local tissue architecture and mixed inflammatory programs. Together, these observations illustrate a paradigm shift from pathway-specific inhibition toward network-informed disease control and highlight key areas for future mechanistic investigation. Full article

Inflammation at the superior airway level has multiple manifestations, and allergic rhinitis and chronic rhinosinusitis with or without polyps are two of the most frequent and troublesome of them, with innate and adaptive immunity being implicated. Dendritic cells, epithelial cells, neutrophils, macrophages, mucosal mast cells, eosinophils, basophils, innate lymphoid cells (ILCs), and NK cells are the players in innate immunity, while regulatory T (Treg), TH1, TH2, TH17, T follicular helper, and B cells are components of the adaptative immune system. Th9 cells, a subset of T helper cells discovered in 2008 that produce interleukin-9 (IL-9), play a vital role in the adaptive immune response and have advantageous and harmful effects in different diseases due to the induction pattern. We queried international databases for current, up-to-date information regarding the interplay between interleukin 9 (IL-9) and helper T cells (especially Th9 cells), and by other immune cells. Interleukin-9 has multiple immunological functions, acting on various target cells through its specific receptor (IL-9R), such as the following: the regulation of allergic (Th2-type) immune responses; effects on epithelial and mucosal cells, mast cells, and eosinophils; chronic inflammation; and autoimmunity. Thus, there is a further need to translate laboratory findings into clinical practice regarding IL-9. Full article

Difficult-to-treat systemic lupus erythematosus (D2T-SLE) remains a major unmet challenge in contemporary lupus care, yet it continues to be defined predominantly by clinical non-response rather than underlying biology. Current biomarkers largely quantify inflammatory burden, immune complex activity, or organ damage and do not reliably capture persistent activation of pathogenic pathways under therapy. Emerging multi-omics, single-cell, and longitudinal studies suggest that, in a subset of patients, apparent treatment failure may reflect incomplete attenuation of dominant immune circuits rather than uniformly elevated inflammation. We propose molecular refractoriness in systemic lupus erythematosus (SLE) as sustained, pathway-level immune activity despite apparently adequate, mechanism-directed therapy. We outline the major immune programs implicated in this process—including interferon-enriched, B-cell/plasmablast-associated, neutrophil extracellular trap (NET)-related, cytotoxic T-cell, and cytokine-associated states—and discuss their relevance for biomarker development and precision trial design. Importantly, we emphasize that interferon gene signatures (IGS) should be interpreted as context-dependent and non-specific markers of interferon responsiveness, reflecting combined activity of type I, II, and III interferons, and functioning primarily as predictive rather than mechanistic biomarkers. We further highlight critical limitations of a purely endotype-based model, including the need to distinguish true molecular refractoriness from damage-dominant and pseudo-refractory states, as well as the emerging role of immune-reset strategies such as cluster of differentiation 19 (CD19)-directed chimeric antigen receptor T-cell (CAR-T) therapy, which may overcome refractoriness independently of specific pathway dominance. These observations suggest that difficult-to-treat SLE encompasses biologically heterogeneous states that may not be fully captured by pathway-resolved stratification alone. Reframing D2T-SLE as a biologically heterogeneous state of incomplete immune attenuation may help bridge the gap between clinical treatment failure and mechanism-informed precision medicine in systemic lupus erythematosus. Full article

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis and Crohn’s disease, are associated with an increased risk of colorectal cancer through mechanisms driven by persistent mucosal inflammation. Chronic inflammatory signaling, recurrent epithelial injury, and altered tissue repair processes progressively reshape the intestinal microenvironment, promoting genomic instability and facilitating the development of colitis-associated colorectal cancer (CAC). Despite the well-established link between inflammation and tumorigenesis, only a subset of patients with long-standing IBD develops malignancy, highlighting the complexity of the regulatory effects of the ongoing inflammation on the tumor initiation and progression. This review discusses the multifaceted roles of innate and adaptive immune responses in CAC pathogenesis. Innate immune signaling mediated by pattern recognition receptors, particularly Toll-like receptors, integrates microbial and damage-associated signals to activate inflammatory pathways that regulate epithelial proliferation, survival, and tumor-promoting cytokine networks. Tumor-associated macrophages, neutrophils, and myeloid-derived suppressor cells contribute to carcinogenesis by sustaining chronic inflammation, promoting immunosuppression, and remodeling the tumor microenvironment, although under specific conditions these cells can also support antitumor immunity. Innate lymphocyte subsets participate in immune surveillance and epithelial homeostasis, yet may also amplify inflammatory circuits that influence tumor development. Adaptive immune populations further shape CAC evolution, as CD4⁺ T-helper subsets, CD8⁺ cytotoxic T lymphocytes, regulatory T cells, and B cells exert divergent effects depending on cytokine milieu, immune context, and disease stage. Understanding immune-cell plasticity and the molecular pathways governing these processes may facilitate the identification of predictive biomarkers and the development of targeted immunomodulatory strategies aimed at preventing CAC. Full article

Background and Objectives: Cutaneous melanoma (CM) is one of the most aggressive skin malignancies due to its rapid progression and high therapeutic resistance. Growing evidence demonstrates that the tumor microenvironment (TME)—comprising diverse immune, stromal, vascular, and epidermal cell populations alongside various cytokines and growth factors, as well as extracellular matrix (ECM) components—plays a crucial role in tumor heterogeneity, metastatic potential, and response to therapy. This review aims to synthesise current knowledge on the cellular and non-cellular constituents of the CM microenvironment and clarify their contributions to tumor progression, immune evasion, and treatment resistance. Materials and Methods: We conducted a narrative review of recent experimental, clinical, and translational studies investigating melanoma–microenvironment interactions, integrating evidence from in vitro, in vivo, and human tissue analyses. Results: Melanoma exhibits marked intra-tumoral heterogeneity driven by genetic, epigenetic, and microenvironmental influences. Cancer-associated fibroblasts, adipocytes, endothelial cells, and keratinocytes are reprogrammed by melanoma cells to promote invasion, angiogenesis, and metastasis. Immune subsets play divergent roles: neutrophils, M2 macrophages, myeloid-derived suppressor cells, and tolerogenic dendritic cells foster immune suppression, while lymphocytes—particularly CD8⁺ T cells, TFH cells, and B cells —are associated with improved outcomes but often become dysfunctional. ECM remodeling, including collagen deposition, integrin signaling, and increased matrix stiffness, actively remodels the tissue to support tumor growth and immune evasion. Hypoxia-inducible factor (HIF)-mediated signaling drives cell dedifferentiation, angiogenesis, and metabolic changes that contribute to treatment resistance. Consequently, emerging therapeutic strategies are moving beyond targeting tumor cells alone to focus on modulating TME components, counteracting immunosuppression, hypoxia, metabolic reprogramming, and extracellular vesicle signaling. Conclusions: The TME profoundly modulates tumor behavior and therapeutic response. A deeper understanding of the reciprocal interactions between melanoma cells and their microenvironmental components may enable the development of more effective strategies for early detection, prognosis, and personalized therapies. Full article

Background: Psoriasis frequently relapses after treatment withdrawal, consistent with persistent epigenetic programs in lesional immune cells. Lysine acetylation is a reversible regulatory layer linking chromatin accessibility, transcription factor activity, and immune-cell effector programs; yet, its cell-type-resolved landscape and clinical stratification value in psoriasis remain incompletely defined. Methods: We integrated four bulk transcriptome cohorts of psoriatic and healthy skin (746 psoriasis, 515 controls) with two public skin scRNA-seq datasets. A diagnostic acetylation-regulator signature was derived from 33 curated acetylation regulators, and acetylation endotypes were defined by unsupervised clustering. The cell-type-specific expression was mapped at the single-cell resolution. Key regulators were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in an imiquimod-induced psoriasis-like mouse model, and further verified in an independent dataset (GSE136757). Motif enrichment and drug–target mining were used to prioritize transcriptional regulators and candidate epigenetic therapeutics. Results: Sixteen acetylation regulators were differentially expressed in bulk skin, with histone deacetylase (HDAC1) showing the strongest upregulation and lysine acetyltransferase (KAT2A) the strongest downregulation. A 13-gene acetylation signature discriminated psoriasis from controls (area under the curve, AUC 0.886) and separated lesional samples into two acetylation endotypes with divergent pathway states (hypoxia–glycolysis versus oxidative-stress-dominated programs). Single-cell mapping demonstrated immune-restricted acetylation modules, including CREB binding protein (CREBBP)-enriched neutrophils, histone deacetylase 1 (HDAC1)-high cluster of differentiation (CD)8⁺ T cells, and lysine acetyltransferase 6A (KAT6A)/lymphoid enhancer binding factor (LEF1)-enriched CD4⁺ and regulatory T cell (Treg) subsets, coincident with interleukin (IL)-17-related inflammatory programs. In mice, qRT-PCR confirmed the coordinated dysregulation of hub genes and highlighted Hnf1a and Kat6a as reproducible candidates. External validation using the GSE136757 dataset further supports their robust diagnostic performance. Motif analysis nominated interferon regulatory factor (IRF4), YY transcription factor (YY2), and zinc finger protein (ZNF404) as putative transcriptional mediators downstream of acetylation programs, and drug–target mining prioritized epigenetic compounds with subtype-relevant potential, including histone deacetylase (HDAC) inhibitors (e.g., entinostat) and the p300/CREB binding protein (CBP) inhibitor A485. Conclusions: This integrative atlas links acetylation regulators to specific immune compartments, defines acetylation endotypes associated with distinct inflammatory programs, and provides a rationale for stratified epigenetic target selection in psoriasis. Full article

Pulmonary embolism (PE) is biologically heterogeneous. Despite guideline-directed anticoagulation, a subset of patients develops recurrent venous thromboembolism, persistent exertional limitation, residual perfusion defects, and progression to chronic thromboembolic pulmonary disease (CTEPD) or chronic thromboembolic pulmonary hypertension (CTEPH). Conventional risk factors explain much of the index event but incompletely account for thrombus non-resolution and chronic sequelae. Clonal hematopoiesis of indeterminate potential (CHIP)—the age-associated expansion of hematopoietic clones carrying somatic mutations—defines a measurable thrombo-inflammatory endophenotype that is strongly genotype- and clone-size (variant allele frequency; VAF)-dependent. Across human studies, JAK2-CHIP and TET2-CHIP show the most consistent associations with VTE/PE, whereas isolated DNMT3A-CHIP is frequently neutral, and larger clones tend to confer stronger effects. Mechanistically, CHIP can bias myeloid cells toward inflammasome/IL-1β signaling and endothelial activation, increase monocyte tissue factor activity, and promote immunothrombosis with neutrophil extracellular trap (NET) formation. NET-rich thrombi may adopt a dense fibrin–DNA–histone architecture that resists endogenous fibrinolysis, favoring organization and persistence. CTEPH offers a translational window to interrogate this model because thrombotic material and deep phenotyping are accessible. We synthesize genotype- and VAF-resolved clinical and mechanistic evidence using a structured strength-of-evidence framework and propose a pragmatic phenotyping roadmap with testable predictions for prospective post-PE validation. CHIP testing in PE/CTEPH remains investigational and should not currently change standard care. Full article