Search Results (90)

B cells are key drivers of immune dysregulation across systemic autoimmune diseases. Among their progeny, plasmablasts occupy a uniquely revealing niche: short-lived, highly proliferative intermediates that mirror real-time B-cell activation. Their appearance in peripheral blood integrates antigenic stimulation, cytokine-driven differentiation, and aberrant germinal-center dynamics, transforming them into sensitive indicators of ongoing immunological activity. This review synthesizes current knowledge on plasmablast biology and highlights disease-specific phenotypes across systemic lupus erythematosus (SLE), primary Sjögren disease (pSjD), IgG4-related disease (IgG4-RD), ANCA-associated vasculitis (AAV), and rheumatoid arthritis (RA). We incorporate molecular insights from single-cell technologies that have uncovered previously unrecognized plasmablast subsets, metabolic states, and interferon-related signatures with prognostic and mechanistic value. Beyond descriptive immunology, plasmablasts are emerging as dynamic biomarkers capable of informing real-time clinical decisions. One of the most robustly supported applications is the prognostic interpretation of plasmablast kinetics following B-cell-depleting therapies, where early reconstitution patterns consistently predict relapse across multiple autoimmune conditions. As clinical immunology shifts from static serological markers toward kinetic, cell-based monitoring, plasmablast quantification offers a path toward precision immune surveillance. Integrating plasmablast dynamics into routine care may ultimately allow clinicians to anticipate disease flares, time therapeutic reinforcements, and transition from reactive management to preventive intervention. Full article

Drug-induced liver injury (DILI) remains one of the most challenging adverse drug reactions in clinical practice, particularly in its idiosyncratic form, which is not dose-dependent and is largely driven by host-specific immune and genetic factors. Recent genomic studies have revealed strong associations between certain human leukocyte antigen (HLA) alleles and susceptibility to DILI, supporting an immunogenetic mechanism in which drug or metabolite–protein adducts act as neoantigens, triggering aberrant T-cell activation and hepatocellular injury. This review summarizes current evidence on the contribution of HLA polymorphisms to the pathogenesis of idiosyncratic DILI, highlighting allele-specific risk patterns, such as HLA-B*57:01 associated with flucloxacillin, HLA-DRB1*15:01–DQB1*06:02 in amoxicillin–clavulanate, and HLA-B*35:02 in minocycline-induced liver injury. Furthermore, ethnic variability and allele-haplotype interactions are discussed as potential modulators of susceptibility and clinical phenotype. By integrating genetic and immunological insights, the identification of HLA signatures offers promising tools for precision medicine, enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions. Full article

Aberrant signaling pathways of the acquired immune system are implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) phenotypes. Understanding the complex abnormalities of lymphocyte subpopulations in CKD is a prerequisite for elucidating their implication in uremic cardiomyopathy. T cell subsets display various patterns of association with indices of myocardial function in both experimental and clinical CKD models. The role of Tregs in CVD and CKD has attracted significant research interest. Although experimental data suggest a protective role of Tregs from the development of arterial hypertension- and pressure overload-induced myocardial hypertrophy, there might be a change in the regulatory T cell (Treg) phenotype towards a profibrotic one in the settings of CKD and heart failure. Depletion of B lymphocytes is a hallmark of CKD and heart failure, bearing adverse prognostic significance, yet evidence of B lymphocytes’ involvement in the pathogenesis of myocardial damage is currently lacking. Considering that myocardial remodeling is the final outcome of diverse pathogenic processes targeting the heart, the aim of this review is to present the evidence available up to now regarding the role of acquired immune cells in the pathogenesis of the structural and functional alterations of the myocardium in CKD. Full article

ARGONAUTE 1 (AGO1) selectively recruits microRNAs (miRNAs) and some small interfering RNAs (siRNAs) to form an RNA-induced silencing complex (RISC) to regulate gene expressions and also promotes the transcription of certain genes through direct chromatin binding. Complete dysfunction of AGO1 causes extremely serious growth arrest and sterility in Arabidopsis. Here, we characterize an ago1-38 allele with distinctive morphological abnormalities obviously distinguishing it from the other ago1 alleles, such as ago1-25 and ago1-45. The aberrant phenotypes of ago1-38 were completely restored in its transgenic complementation lines harboring an AGO1 promoter and coding sequence. To investigate the mechanism underlying the unique phenotype of ago1-38, integrated transcriptomic and metabolomic analysis was employed. The glutathione metabolism pathway was significantly co-enriched in the integrated analysis of ago1-38, suggesting an altered balance of the glutathione-related redox system. Transcriptomic analysis showed that many genes in the siRNA processing pathway were significantly changed in ago1-38, suggesting the dysregulation of the siRNA pathway. Meanwhile, numerous genes, particularly the large set of transcriptional factors associated with plant–pathogen interaction networks and phytohormone signaling cascades, exhibited altered expression patterns, implying perturbed immune defense and hormonal signaling. Collectively, these findings provide new insights into the multifaceted roles of AGO1 in siRNA processing, pathogen response, and phytohormone signaling. Full article

Antibody-based therapeutics targeting tumor surface markers have transformed cancer treatment; however, their efficacy is frequently limited by tumor escape mechanisms such as antigen loss, phenotypic switching, and heterogeneous target expression. Beyond genetic or transcriptional changes, RNA alternative splicing (AS) has emerged as a central post-transcriptional mechanism driving antigenic diversity and immune escape. This review outlines how AS-generated isoforms remodel surface antigen structure and function across key therapeutic targets—including CD/19/CD20/CD22, EGFR/HER2, VEGF, and PD-1/PD-L1—thereby promoting resistance to monoclonal antibodies, antibody–drug conjugates, and immune checkpoint inhibitors. The aberrant activity of splicing regulators disrupts canonical exon selection, leading to altered receptor signaling or the secretion of soluble decoy isoforms that evade immune recognition. Emerging therapeutic strategies aim to counteract these processes through antisense oligonucleotide-mediated splicing correction, pharmacologic modulation of splicing regulators, and isoform-selective antibody or CAR-T designs. Collectively, understanding splicing-driven antigenic plasticity reveals an additional, dynamic layer of resistance regulation and provides a framework for developing RNA-informed precision antibody therapies designed to restore antigen expression, overcome immune escape, and enhance durable clinical responses. Full article

People with HIV (PWH) are at an increased risk for AIDS-associated non-Hodgkin lymphoma (AIDS-NHL); however, the immune signatures underlying this risk are not well understood. In this study, we utilized mass cytometry by time-of-flight (CyTOF) to analyze T-cells and monocytes in the PBMCs of treatment-naïve PWH, including those 3 to 36 months before an AIDS-NHL diagnosis (HIV-positive pre-NHL), as well as people without HIV (PWoH). Mass cytometry is an advanced single-cell analysis platform that combines flow cytometry principles with mass spectrometry. Unlike conventional flow cytometry, this technology employs antibodies conjugated to unique metal isotopes instead of fluorescent markers, enabling simultaneous measurement of over 40 distinct cellular markers per individual cell without spectral overlap limitations. Participants were enrolled at the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Unsupervised clustering and Uniform Manifold Approximation and Projection (UMAP) analysis identified CD3⁺ T-cell and CD14⁺ monocyte metaclusters, and Spearman’s rank correlation assessed their relationships with B-cell subsets exhibiting aberrant phenotypes. We observed elevated levels of CD8⁺CD20⁺ T-cells, CD8⁺CD14⁺ T-cells, and M2-like CD14⁺CD163⁺ monocytes in HIV-positive pre-NHL individuals compared to HIV-negative controls. Positive correlations were found between CD19⁺ AICDA⁺ cMYC⁺ B-cells and M1-like CD14⁺cMYC⁺ monocytes (metacluster, MC02), and between metaclusters of CD8⁺PD-1⁺CD27⁺CXCR4⁻ T-cells (MC05) and CD4⁺FoxP3⁺PD-1⁺CD27⁺CD28⁺CXCR4⁻ ICOS⁺ T-cells (MC08). In addition, a different CD19⁺ B-cell metacluster (FoxP3⁺AICDA⁺cMYC⁺) was positively associated with a metacluster of CD8⁺PD-1⁺CD27⁺CD28⁺CXCR4⁺ T-cells (MC03). Moreover, the metacluster of CD8⁺PD-1⁺CD27⁺CXCR4⁻ T-cells (MC05) negatively correlated with M2-like CD14⁺CD163⁺ monocytes (MC06), while CD8⁺CD14⁺ T-cells positively correlated with AICDA⁺ Bregs and IL-10⁺ B-regs in HIV-positive pre-NHL individuals. Unsupervised analysis revealed increased frequencies of CD8⁺CD20⁺ T-cells in HIV-positive individuals compared to HIV-negative controls. These immune alterations provide valuable insights into potential biomarkers for early detection, monitoring, and therapeutic strategies for AIDS-NHL. Full article

Interferons (IFNs) are key cytokines at the intersection of innate and adaptive immunity. While their antiviral and antitumor roles are well recognized, emerging evidence implicates IFNs—particularly types I, II, and III—in the initiation and progression of autoimmune diseases (ADs). This review synthesizes current data on IFN biology, their immunoregulatory and pathogenic mechanisms, and their contributions to distinct AD phenotypes. We conducted a comprehensive review of peer-reviewed literature on IFNs and autoimmune diseases, focusing on publications indexed in PubMed and Scopus. Studies on molecular pathways, immune cell interactions, disease-specific IFN signatures, and clinical correlations were included. Data were extracted and thematically organized by IFN type, signaling pathway, and disease context, with emphasis on rheumatic and systemic autoimmune disorders. Across systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, idiopathic inflammatory myopathies, multiple sclerosis, type 1 diabetes, psoriasis, and inflammatory bowel diseases, IFNs were consistently associated with aberrant activation of pattern recognition receptors, sustained expression of interferon-stimulated genes (ISGs), and dysregulated T cell and B cell responses. Type I IFNs often preceded clinical onset, suggesting a triggering role, whereas type II and III IFNs modulated disease course and severity. Notably, IFNs exhibited dual immunostimulatory and immunosuppressive effects, contingent on tissue context, cytokine milieu, and disease stage. IFNs are central mediators in autoimmune pathogenesis, functioning as both initiators and amplifiers of chronic inflammation. Deciphering the context-dependent effects of IFN signaling may inform targeted therapeutic strategies and advance precision immunomodulation in autoimmune diseases. Full article

Acute myeloid leukemia (AML), the most common acute leukemia among adults, poses significant therapeutic challenges due to diagnostic limitations and the frequent development of treatment resistance. While genomics-based approaches have advanced, DNA aberrations do not always reflect the expression levels of genes and proteins, which are more tightly connected to disease phenotypes. Recently, the role of the gut microbiota in AML has gained increasing attention. AML patients often exhibit gut microbiota dysbiosis, which is linked to disease progression and heightened infection risk. Mounting evidence indicates that gut microbiota metabolism influences hematopoiesis and immune function via the “gut-bone marrow axis,” with microbiota composition and diversity significantly affecting treatment outcomes and prognosis. High-throughput sequencing and metabolomics have identified correlations between gut microbiota composition and its metabolic products with AML clinical characteristics, paving the way for new biomarkers in diagnosis and prognosis. Additionally, treatments such as fecal microbiota transplantation (FMT) show promise in enhancing chemotherapy efficacy and improving patient outcomes. This review highlights recent advances in understanding the role of the gut microbiota in AML and explores new perspectives for its diagnosis and treatment. Full article

Background/Objectives: Restored CD4 absolute counts (CD4AC) and CD4/CD8 ratio in the setting of continuous antiretroviral treatment (ART) do not exclude a low-level immune activation associated with HIV reservoirs, microbial translocation, or the side effects of ART itself, which accelerates the aging of people living with HIV (PLHIV). To delineate biomarkers of incomplete immune restoration in PLHIV on successful ART, we evaluated T-lymphocyte mitochondrial parameters in relation to phenotypic markers of immune exhaustion and senescence. Methods: PLHIV with sustained viral suppression, CD4AC > 500 and CD4/CD8 ratio >0.9 on ART (n = 39) were compared to age-matched ART-naïve donors (n = 27) and HIV(–) healthy controls (HC, n = 35). CD4 and CD8 differentiation and effector subsets (CCR7/CD45RA and CD27/CD28), activation, exhaustion, and senescence markers (CD38, CD39 Treg, CD57, TIGIT, and PD-1) were determined by flow cytometry. Mitochondrial mass (MM) and membrane potential (MMP) of CD8 and CD4 T cells were evaluated with MitoTracker Green and Red flow cytometry dyes. Results: ART+PLHIV differed from HC by increased CD4 TEMRA (5.3 (2.1–8.8) vs. 3.2 (1.6–4.4), p < 0.05), persistent TIGIT+CD57–CD27+CD28– CD8+ subset (53.9 (45.5–68.9) vs. 40.1 (26.7–58.5), p < 0.05), and expanding preapoptotic TIGIT–CD57+CD8+ effectors (9.2 (4.3–21.8) vs. 3.0 (1.5–7.3), p < 0.01) in correlation with increased CD8+ MMP (2527 (1675–4080) vs.1477 (1280–1691), p < 0.01). These aberrations were independent of age, time to ART, or ART duration, and were combined with increasing CD4 T cell MMP and MM. Conclusions: In spite of recovered CD4AC and CD4/CD8 ratio, the increased CD8+ MMP, combined with elevated markers of exhaustion and senescence in ART+PLHIV, signals a malfunction of the CD8 effector pool that may compromise viral reservoir latency. Full article

Oxysterols such as 7-ketocholesterol (7KCh) contribute to the pathogenesis of autoimmune and chronic inflammatory diseases by inducing oxidative stress and promoting pro-inflammatory immune cell activation. Dendritic cells (DCs) play a central role in maintaining immune tolerance, and their dysregulation is a key driver of autoimmunity. Targeting DCs by using natural compounds offers a promising strategy to restore redox balance and suppress aberrant immune responses. This study investigated the immunomodulatory and antioxidant properties of Lupeol, a natural triterpenoid, in human monocyte-derived DCs exposed to 7KCh. Flow cytometry and cytokine profiling demonstrated that Lupeol preserved the immature, tolerogenic phenotype of DCs by promoting a dose-dependent increase in the anti-inflammatory cytokine IL-10. Lupeol also inhibited the 7KCh-induced upregulation of maturation markers (CD83, CD86) and suppressed the release of pro-inflammatory cytokines IL-1β and IL-12p70. Functionally, Lupeol-treated DCs directed T cell polarization toward an anti-inflammatory and regulatory profile while dampening the inflammatory responses triggered by 7KCh. This immunoregulatory effect was further supported by the decreased secretion of the pro-inflammatory cytokines IL-1β and IL-12p70 in DC culture supernatants. Mechanistic analyses using immunofluorescence showed that Lupeol alone significantly increased nuclear NRF2 levels and upregulated HO-1 expression. Western blot analysis further confirmed Lupeol’s ability to activate the KEAP1-NRF2 signaling pathway, as evidenced by increased expression of NRF2 and its downstream target, NQO1. The use of ML385, a selective NRF2 inhibitor, in ROS and cytokine assays supported the involvement of NRF2 in mediating the Lupeol antioxidant and anti-inflammatory effects in DCs. Notably, the oxidative burden induced by 7KCh limited the full activation of NRF2 signaling triggered by Lupeol. Furthermore, docking and MM/PBSA analyses revealed the specific interactions of Lupeol with the kelch domain of KEAP1. These findings suggest that Lupeol may serve as a promising orally available immunomodulatory agent capable of promoting tolerogenic DCs, offering potential applications in autoimmune and other chronic inflammatory diseases. Full article

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal–fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron–immune axis, encompassing three key modalities—iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions—which may offer novel avenues for PE prevention and treatment. Full article

Heterotopic ossification (HO) refers to an abnormal process characterized by the aberrant development of bone within soft tissues, leading to significant impairments in patients’ mobility and overall quality of life. Macrophages, as a crucial element of the immune system, are instrumental in the different stages of heterotopic ossification through their dynamic polarization state (pro-inflammatory M1 and anti-inflammatory M2 phenotypes) and secretion of different cytokines. This review explores novel mechanisms of M1 and M2 macrophage-mediated heterotopic ossification, emphasizing the involvement of the inflammatory microenvironment, osteogenic factors, and osteogenic signaling pathways. In addition, we explore promising therapeutic strategies targeting macrophage polarization and function, including agents that modulate the inflammatory microenvironment, such as IL-1 inhibitors, parovastatin, and metformin, as well as agents that affect macrophage osteogenic signaling, such as TGF-βRII-Fc, Galunisertib, and Ruxolitinib. A more comprehensive understanding of these mechanisms may open up new avenues for developing novel approaches to reducing HO in high-risk patients. Full article

Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review explores the mechanisms underlying SMARCB1 aberrations, their role in driving hallmarks of cancer, and emerging therapeutic strategies for RTs. Ongoing clinical trials listed on ClinicalTrials were reviewed to evaluate the translational potential of targeted therapies in SMARCB1-deficient rhabdoid tumours. Results: Loss of SMARCB1 drives multiple cancer hallmarks by disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations in p16INK4a and Myc signalling. SMARCB1-deficient tumours possess immune-evading capabilities via PD-L1 overexpression and immune checkpoint activation. SMARCB1 deficiency also alters cellular energetics. The nucleotide biosynthesis pathway has been demonstrated to be upregulated in RT organoids, as shown by increased levels of pathway metabolites. Enzymes of the mevalonate pathway such as HMG-CoA reductase and mevalonate kinase are also dysregulated. Targeting glutathione metabolism with eprenetapopt may induce oxidative stress and apoptosis. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat. Conclusions: SMARCB1 loss is a central driver of cancer hallmarks in RTs, enabling proliferation, immune evasion, metabolic reprogramming, and epigenetic dysregulation. Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment requires further characterisation for clinical translation. Full article

Background/Objectives: Melanoma remains a difficult malignancy to treat because it employs tolerance mechanisms like negative immune checkpoint (IC) molecules to avoid antitumor immune responses. Thus, immune checkpoint inhibitors (ICIs) are increasingly used to treat melanoma. However, many patients do not respond, indicating resistance mechanisms like intrinsic tumor characteristics and an immunosuppressive tumor microenvironment (TME). An inflamed TME was associated with improved ICI efficacy by upregulating the T-cell inflamed TME gene signatures, an array of genes associated with dendritic cells (DCs) and cytotoxic CD8⁺ T-cell-mediated anti-tumor responses. As histone deacetylases (HDACs) have been shown to play crucial roles in regulating gene expression and aberrant HDAC expression has been reported in melanoma and also implicated in the regulation of IC, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) and various immune evasion genes, we investigated the relationship between T-cell inflamed TME gene signatures and the HDAC family, particularly HDAC4. Methods: We used the skin cutaneous melanoma (SKCM) database, ICI-pretreated melanoma dataset, and other platforms including cBioPortal, TIMER 2.0, TISIDB, and UALCAN for the analysis. Results: We identified that high HDAC4 expression negatively modulated the TME by decreasing the abundance of DCs and cytotoxic CD8⁺ T-cells. The group of melanoma patients with elevated HDAC4 expression exhibited not only poor prognosis but also diminished transcription of T-cell inflamed TME gene signatures and increased DNA methylation of T-cell inflamed TME gene signatures. Importantly, elevated HDAC4 expression was associated with decreased CD8⁺ T-cells and a decreased ESTIMATE immune score in ICI-pretreated melanoma patients. Conclusions: Our findings suggest that HDAC4 may transform the TME into a non-inflamed phenotype, thereby reducing ICI efficacy in melanoma. Overall, this research shows that a combination of HDAC4 inhibitors and ICIs could result in better melanoma prognosis. Full article