Gardnerella vaginalis, an important bacterial pathogen associated with bacterial vaginosis, produces bacterial extracellular vesicles (bEVs), which can contribute to cellular pathogenesis. However, comprehensive host-microbe crosstalk mechanisms such as cellular entry route, after internalization, and host cytoskeleton modifications remain poorly characterized. In this study, we treated female reproductive tract cell lines with G. vaginalis and its vesicles. To evaluate their entry routes, host cells were pretreated with pharmacological inhibitors and treated with labelled bacterial cells or derived vesicles. Next, to delineate the endolysosomal processing routes, vaginal epithelial cells were stained to enable the visualization of endosomal and lysosomal compartments. The results revealed that G. vaginalis and its vesicles were internalized in vaginal epithelial cells and followed nonspecific and caveolin-dependent endocytosis, respectively. Confocal imaging showed that while internalized vesicles trafficked to intracellular compartments, consistent with the endolysosomal pathway, the G. vaginalis underwent noncanonical processing, suggesting a possible escape from cellular degradation. Of note, vesicles mediated F-actin rearrangements consistently in all female genital tract cells while G. vaginalis exhibited this phenomenon only in non-vaginal cells. These novel findings of entry routes, intracellular fates, and G. vaginalis- and vesicle-mediated cytoskeletal changes in host cells advance our understanding of cellular pathogenesis associated with bacterial vaginosis.
Advances in organoid and other three-dimensional culture systems, single-cell and spatial transcriptomics, multi-omics, and high-resolution imaging are reshaping our understanding of the cellular origins and evolutionary trajectories of glioblastoma. When integrated with modern data science approaches, these technologies enable the construction of increasingly detailed molecular biographies of normal neural stem and progenitor cells as well as malignant stem-like cellular states. Such molecular biographies illuminate how developmental programs, cellular plasticity, and microenvironmental cues are co-opted during gliomagenesis. At the same time, progress in machine learning, immunotherapy, and precision molecular targeting is beginning to translate these biological insights into therapeutic strategies that specifically disrupt glioblastoma stem-like states. Together, these converging approaches provide a conceptual and technological framework for improved tumor modeling, earlier detection, and increasingly personalized therapies for malignant gliomas.
The Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) are frequently linked to neuropsychiatric illnesses such as multiple sclerosis, depression, and chronic fatigue syndrome/myalgic encephalomyelitis. These viruses may induce autoimmune reactions by molecular mimicry, leading to damage to self-epitopes in the central nervous system (CNS). This study seeks to explore the common pentapeptides present in EBV and HHV-6 viral antigens alongside various CNS-related proteins via molecular mimicry. Additionally, it will assess the immunogenicity of these shared pentapeptides in T and B cells. Sequence alignment was conducted to assess molecular mimicry between 32 EBV and HHV-6 antigens and 10 CNS autoantigens. Protein sequences were obtained from UniProt, structural homology was analyzed using AlphaFold and PyMol, and shared pentapeptides were identified with Alignmentaj. Immunogenicity was assessed via the Immune Epitope Database (IEDB) for potential T- and B-cell activation. A total of 91 mimicry pentapeptides were identified between viral antigens (42 EBV and 49 human HHV-6), and 10 CNS proteins. Notably, synapsin (SYN)1 exhibited the highest mimicry, sharing 13 pentapeptides with (7 with EBV and 6 with HHV-6) viral antigens such as EBV nuclear antigen (EBNA)1, EBNA6, latent membrane protein (LMP)1, and early antigen diffused (EA-D). Myelin proteins, including myelin-associated glycoprotein with 12 shared pentapeptides, myelin basic protein with 9, and myelin-oligodendrocyte glycoprotein with 5, displayed immune cross-reactivity with EBV/HHV-6 antigens. EBNA1, EBNA2, EBNA6, LMP1, LMP2, EA-D, and BLLF1 structurally resemble CNS autoantigens and act as immunoreactive epitopes for human T and B cells. Except for EBNA2 and protein U94, all share immunogenic pentapeptide sequences with SYN1. Shared pentapeptides suggest a link between viral infections and CNS autoimmunity. Further research is needed to clarify molecular mechanisms and explore targeted therapies to mitigate virus-induced neuroinflammation.
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) is a rare, distinct subtype of pancreatic carcinoma, formally classified separately from undifferentiated carcinoma (UC) of the pancreas in the World Health Organization's 2010 and 2019 revisions. Whereas classic UC is associated with a poor prognosis and low survival rates, recent studies suggest that patients with UCOGC experience significantly longer survival and more frequent diagnosis at surgically resectable stages. Molecular profiling reveals that UCOGC consistently harbors canonical mutations in KRAS, CDKN2A, TP53, and SMAD4, aligning its classification within pancreatic ductal adenocarcinoma. In addition, UCOGC demonstrates a heterogeneous molecular landscape with distinctive mutations of uncertain biological relevance. Immunologically, UCOGC is characterized by a unique tumor microenvironment, notably a deficiency in regulatory T cells (Tregs) and a relative abundance of antigen-presenting cells. Elevated expression of PD-1 within UCOGC further suggests a potential for enhanced response to PD-1-targeted immunotherapies. Collectively, these findings underscore the need for ongoing research into the molecular and immunological characteristics of UCOGC, with the aim of identifying novel biomarkers and developing targeted treatment strategies.
SERPINA12 is a member of the serpin superfamily that has been extensively studied in metabolic and inflammatory disorders. In recent years, increasing evidence has highlighted its emerging role in skin physiology and dermatological diseases. SERPINA12 is expressed in multiple skin cell types, including keratinocytes and dermal fibroblasts, where it participates in the regulation of inflammation, cellular proliferation, differentiation, and tissue homeostasis. Dysregulation of SERPINA12 has been implicated in several skin disorders. In psoriasis, altered SERPINA12 expression is associated with chronic inflammation, immune dysregulation, and abnormal keratinocyte proliferation, suggesting a potential modulatory role in psoriatic pathogenesis. Furthermore, emerging studies suggest a possible involvement of SERPINA12 in palmoplantar keratoderma, where it may contribute to aberrant keratinization and epidermal barrier dysfunction. This review summarizes current knowledge on the expression patterns, biological functions, and molecular mechanisms of SERPINA12 in the skin, with a particular focus on adipocytes, psoriasis, and palmoplantar keratoderma. Understanding the role of SERPINA12 in cutaneous biology may provide new insights into disease pathogenesis and identify potential therapeutic targets for skin disorders.
Sjögren's Disease is an autoimmune epithelitis targeting the exocrine glands, predominantly the salivary and lacrimal glands, resulting in the major symptoms of dry mouth and dry eyes. The aim of this study is to review the pertinent literature on studies linking the oral manifestations of SjD patients, with the underlying molecular events driving SjD pathogenesis. These include mechanisms inducing innate sensing in salivary gland epithelial cells, activation of interferon signaling pathway, amplification of cytokines and chemokines, and orchestration of the inflammatory milieu in salivary glands, as well as mechanisms inducing salivary epithelial tissue destruction and secretory dysfunction, such as programmed cell death pathways, mitochondrial dysfunction, structural disorganization, loss of junctional integrity, and quantitative and qualitative aberrations in salivary secretory process.
CD20 × CD3 bispecific antibodies (BsAbs) have emerged as a meaningful therapeutic option for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), redirecting endogenous T cells against malignant B cells independently of major histocompatibility complex-mediated antigen presentation, and have received regulatory approval after at least two prior lines of therapy. However, a substantial proportion of patients experience primary resistance or early relapse, underscoring the need to characterize the underlying biological mechanisms, which are the focus of this review. Several tumor-intrinsic determinants of resistance have been identified, including CD20 loss driven by MS4A1 mutations, alternative splicing, and gene deletion, as well as genomic reprogramming involving TP53, MYC, and NOTCH1 alterations. T-cell dysfunction represents another critical resistance domain, encompassing inadequate intratumoral cytotoxic CD8+ T-cell infiltration, expansion of immunosuppressive regulatory and follicular helper T cells, progressive exhaustion with upregulation of PD-1, LAG-3, TIM-3, and TIGIT, and impaired T-cell fitness from prior treatment exposure. Microenvironmental barriers, including checkpoint ligand upregulation, PD-L1-enriched extracellular vesicles, spatial exclusion of effector cells from immune-cold germinal center-like niches, hypoxia, and metabolic competition, further reinforce immune escape. Emerging strategies to overcome resistance include epigenetic priming, checkpoint inhibitor combinations, 4-1BB costimulatory approaches, and next-generation multispecific antibody designs.
Since MDCK cells are inherently tumorigenic, their safety in vaccine production has long been a concern; thus, establishing a screening method for low-tumorigenic cells is of great significance for influenza vaccine development. This study successfully obtained a low-tumorigenic MDCK cell line through monoclonal screening and systematically evaluated its potential as a cellular substrate for influenza vaccines using male nude mice (BALB/c nu/nu, 4-7 weeks old) for tumorigenicity assessment. Comprehensive analysis of the biological characteristics of the screened cells-including growth curves and transcriptomic features-showed that the cell line exhibits stable growth and consistent traits. Transcriptomic comparison was performed between two defined biological states: parental MDCK cells (SQ group) and the low-tumorigenic clone MDCK-20B9 (SH group). Transcriptomic analysis revealed good dispersion among samples and an overall consistent gene expression distribution. Differential expression analysis identified a total of 2198 differentially expressed genes, including 902 upregulated and 1296 downregulated genes. GO functional enrichment analysis indicated that these genes are mainly involved in biological processes such as acute-phase response, retinol metabolism, mitotic chromosome condensation, and cell migration; are enriched in cellular components such as kinetochores and the extracellular matrix; and are associated with molecular functions including calcium ion binding and the Wnt signaling pathway. KEGG pathway analysis further revealed that the differentially expressed genes are significantly enriched in key pathways such as cancer pathways, cell cycle, and cell adhesion molecules. The expression trends of five key differentially expressed genes were validated by RT-qPCR. In summary, this study successfully screened a stable and consistent low-tumorigenic MDCK cell line, providing a theoretical basis and practical foundation for its use as a cellular substrate in influenza vaccine development.
Tungsten is an emerging environmental contaminant, highlighting the urgent need to elucidate its toxicological characteristics and assess long-term health risks. Our previous investigations show that tungsten deposition in the bone is associated with stalled pre-B lymphocyte differentiation, inhibition of osteogenesis, and increased intervertebral disc degeneration and fibrosis. To delineate the underlying molecular mechanisms, we employed CRISPR-based genomics on NALM-6 cells and identified Solute Carrier Family 26 Member 2 (SLC26A2), a sulfate/chloride antiporter, as a pivotal mediator of tungsten-induced toxicity. SLC26A2 deletion reduced tungsten-induced growth inhibition and intercellular tungsten levels. Functional impairment of SLC26A2 is associated with chondrodysplasias, thus, we hypothesized that tungsten would impair the development of cartilage and bone tissues. Indeed, tungstate exposure impaired chondrogenesis and osteogenesis in murine limb cultures, which was reversible by sulfate supplementation. Our study demonstrates that tungsten exploits SLC26A2 for cellular entry and correlates with bone development disruption through proteoglycan and collagen depletion.
Glioblastoma (GBM) remains one of the most challenging forms of cancer to treat, despite that extensive molecular profiling is now available. Indeed, intratumoral cellular heterogeneity, receptor redundancy, and adaptive resistance through compensatory signaling limit the impact of targeted therapies. Moreover, immunotherapies also underperform: checkpoint blockade and vaccine strategies did not obtain consistent benefits in a low mutational burden, poorly immunogenic tumor microenvironment (TME) dominated by immunosuppressive myeloid cells. In this article, we provide evidence that tumor-associated macrophages (TAMs), a form of CNS resident microglia and infiltrating macrophage, derived from bone marrow, adopt a spatially and transcriptionally distinct, non-binary continuum, shaped by tumor-derived signals and niche constraints, allowing glioma cells to resist to immune and pharmaceutical therapeutics. Metabolic rewiring, including hypoxia-linked glycolytic pressure, lactate signaling, and lipid-associated programs, determine immunosuppressive outputs and restrict plasticity, while epigenetic imprinting (DNA methylation, histone modifications, and chromatin regulators) stabilizes these programs and limits access to inflammatory loci. We discuss how stem cell secretome, and extracellular vesicles (EVs) and their cargo may act as tunable autocrine/paracrine inputs that may bias microglial regulatory control. Finally, we highlight major translational confounders, including EV operational definitions, blood-brain barrier (BBB) permeability and regional exposure, inconsistent dosing units, mixed myeloid compartments, and manufacturing dependent variability. Therefore, an exposure-aware framework that integrates product identity, delivery evidence, state-sensitive potency assays, and functional endpoints would be highly desirable.
Escherichia coli constitutively release nano-sized outer membrane vesicles (OMVs) containing numerous virulence factors and immunomodulatory proteins. In this research, we demonstrate that OMVs isolated from the E. coli readily entered Raw 264.7 macrophages and were randomly dispersed within the cytoplasm, and therefore able to deliver their molecular cargos to host cells. With electron microscopy, it can also be observed that OMVs attached to the cell surface or existed in the membrane vesicles of the cell. E. coli-OMVs proved to be non-toxic and had no obvious negative impact on the viability of macrophage cells when the concentration ranged from 1 to 10 µg/mL. The OMVs were targeted to mitochondria of Raw 264.7 macrophage, which was accompanied by elevated intracellular reactive oxygen species levels, activated autophagy, and a marked reduction in intracellular ATP levels-a hallmark of mitochondrial dysfunction. Consistent with this, E. coli-OMVs induced massive and dose-dependent proinflammatory responses in macrophage cells. Altogether, these results indicated that E. coli exploits OMVs to target virulence factors and immunomodulatory proteins to host cells, triggering mitochondrial dysfunction, autophagy, and proinflammatory responses, thus consequently affecting host-pathogen interactions in course of infection.
Chronic psychological stress is a well-recognized factor in the exacerbation of allergic diseases, with IgE playing a central role in their pathophysiology. However, the exact molecular mechanisms by which stress hormones directly influence IgE production and contribute to allergic responses remain largely uncharacterized. This study aimed to elucidate the direct mechanisms through which chronic psychological stress, via elevated cortisol, regulates IgE class switch recombination (CSR) in B cells and contributes to stress-aggravated allergic inflammation in vivo. We employed a chronic restraint stress (CRS) mouse model to investigate the impact of psychological stress on humoral immunity. In vitro experiments utilized primary murine B cells treated with physiological cortisol concentrations (250 nM), incorporating molecular techniques such as CRISPR-Cas9-mediated gene knockdown, chromatin immunoprecipitation (ChIP), whole-genome bisulfite sequencing, and pharmacological inhibitors of epigenetic enzymes. Primary human B cells and the U266 human myeloma cell line were used for translational validation. In vivo validation was performed using an ovalbumin (OVA)-induced allergic airway inflammation model with B cell-specific glucocorticoid receptor (GR) knockout mice. Chronic psychological stress significantly elevated plasma corticosterone and serum IgE levels in mice, with no changes in IgG1 or IgM. In purified in vitro B-cell cultures, cortisol promotes epigenetic remodeling at the Iε promoter region and enhances Iε germline transcript expression in an isotype-specific manner, and this effect was recapitulated in human B cells. GR bound to the Iε promoter's Amp_1 region (-154 to -62 bp), and CRISPR-Cas9-mediated GR knockdown abolished cortisol-induced IgE production. Mechanistically, cortisol increases enrichment of activating histone marks (H3K27ac, H3K4me3) and reduces H3K27me3 at the Iε promoter region, and induces site-specific DNA hypomethylation; inhibition of histone acetyltransferases (HATs) or DNA demethylation attenuated this effect. In vivo, B cell-specific GR knockout completely abrogated stress-induced exacerbation of allergic airway inflammation, including elevated serum IgE, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Our findings support a mechanistic model in which chronic psychological stress, through elevated glucocorticoids, acts via GR to promote epigenetic remodeling at the Iε promoter region in B cells to enhance IgE synthesis and exacerbate allergic responses. This study provides a critical molecular link between the neuroendocrine system and adaptive immunity, offering promising therapeutic targets for stress-aggravated IgE-mediated diseases.
Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.
Acute respiratory distress syndrome (ARDS) is associated with high mortality and complex pathophysiology, yet molecularly targeted therapies remain undeveloped. In particular, the microRNA (miRNA)-mRNA regulatory network underlying ARDS is poorly understood. This study aimed to elucidate the miRNA-mRNA interactions associated with the pathophysiology of ARDS. mRNA-Seq and miRNA-Seq were performed in 34 patients with ARDS and healthy controls. Gene and miRNA co-expression modules were constructed using Weighted Gene Co-expression Network Analysis. miRNA-mRNA regulatory relationships were inferred through an integrated analysis of predicted and experimentally validated miRNA targets. Molecular signatures were quantified via single-sample gene set enrichment analysis, and module structure preservation was evaluated in an external pneumonia cohort. A key mRNA co-expression module was identified that exhibited the strongest negative correlation with the P/F ratio, along with a negatively correlated miRNA co-expression module. The miRNA module, centered on miR-361-5p and miR-186-5p, formed a regulatory network broadly controlling gene clusters involved in ubiquitin ligase activity and cellular stress response pathways. This network demonstrated a strong association with the P/F ratio and showed high structural preservation in the external pneumonia cohort. A miRNA-mRNA regulatory network linked to impaired oxygenation in patients with ARDS has been identified. The network highlights miRNAs as potential key regulators of disease progression and suggests their utility as biomarkers of disease severity and prospective therapeutic targets.
Type II toxin-antitoxin (TA) systems are significantly expanded in the Mycobacterium tuberculosis complex; however, the functional role of the VapBC40 system in Mycobacterium bovis (M. bovis) pathogenesis remains poorly characterized. This study aimed to investigate the role of VapBC40 in mycobacterial virulence and evaluate its potential as a target for rational vaccine attenuation. We performed evolutionary analysis and yeast two-hybrid assays to characterize VapBC40 system specificity, conducted in vitro macrophage infection models and in vivo murine studies to assess virulence contribution, and evaluated the immunoprotective efficacy of a VapC40 knockout strain. Evolutionary analysis revealed progressive sequence conservation and stringent homologous pairing specificity within the VapBC40 system. The VapC40 toxin correlates with enhanced intracellular bacterial survival, increased host cell death, and more severe pulmonary pathology with systemic dissemination. Based on these findings, we evaluated the vaccine potential of a vapC40 knockout strain. Immunization with this attenuated strain elicited a Th1 cellular immune response, characterized by enhanced IFN-γ production and increased frequency of CD4+IFN-γ+ T cells. Upon challenge with virulent M. bovis, the knockout strain conferred superior protection compared to the conventional BCG vaccine, significantly reducing lung pathology and restricting extrapulmonary bacterial dissemination. Although the molecular mechanisms underlying VapC40-mediated effects remain to be fully elucidated, our findings suggest an important role of the VapBC40 system in mycobacterial-host interactions and support its potential as a target for next-generation tuberculosis vaccine development.
Cardiovascular diseases remain the leading cause of mortality worldwide, and one of the key mechanisms driving the development of heart failure is pathological remodeling of the myocardium. This process involves complex structural, cellular, and metabolic alterations in which the immune system and its interactions with cardiomyocytes and fibroblasts play a central role. The aim of this work was to present the current state of knowledge on immunometabolism in cardiac remodeling and to discuss its pathophysiological relevance and therapeutic potential. This review focuses on the metabolism of cardiac macrophages, highlighting the differences between the pro-inflammatory (M1) and reparative (M2) phenotypes and their impact on inflammation, fibrosis, and myocardial regeneration. The roles of major metabolic pathways, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, are discussed, as well as the importance of the NLRP3 inflammasome and efferocytosis in regulating the inflammatory response. Furthermore, the review briefly incorporates recent insights into neutrophil, T cell, and regulatory T cell (Treg) metabolism and their contributions to inflammation, repair, and fibrotic remodeling. Particular attention is also given to cardiac fibroblasts and their metabolic reprogramming during fibrosis, with emphasis on the pivotal role of transforming growth factor-β (TGF-β) signaling. The review further discusses the role of microRNAs as mediators of intercellular communication integrating immunological and metabolic signals. The work is complemented by a discussion of therapeutic perspectives, including modulation of macrophage metabolism, fibrogenic signaling pathways, mitochondrial function, and miRNA-based therapies. Immunometabolism emerges as a promising research field whose further exploration may contribute to the development of novel, more precise strategies for the treatment of cardiovascular diseases.
The ammonia signaling network plays a central role in the tumor microenvironment. It has evolved from a traditional concept of metabolic waste into a critical signaling molecule that profoundly promotes the progression of malignant tumors by regulating metabolic remodeling, epigenetic modifications, and tumor metastasis. As research continues to deepen, scientists have gradually revealed the molecular mechanisms of the ammonia signaling network in tumorigenesis and evolution, although a comprehensive understanding remains to be achieved. This network not only regulates the metabolic state of tumor cells but also enhances their migratory capacity by orchestrating epigenetic changes, thereby driving tumor metastasis and immune evasion. This article aims to systematically elucidate the significance of the ammonia signaling network in tumor metabolic dysregulation and epigenetic remodeling, delve into its role in the process of tumor metastasis, and ultimately outline potential therapeutic strategies targeting this network. By linking metabolism, epigenetics, and immunology, the ammonia signaling network provides a unified paradigm for understanding tumor biology and offers new insights and directions for future research and clinical interventions.
Hereditary angioedema (HAE) with C1-esterase inhibitor (C1INH) deficiency is caused by variants in the SERPING1 gene. A decrease in C1INH function results in overproduction of bradykinin, causing enhanced vascular permeability and swelling. The signal peptide (SP) is essential for C1INH secretion. While SP variants in the SERPING1 gene have been reported, their genotype-phenotype correlations have not been well characterized. To investigate the impact of SP variants, we systematically evaluated 33 SP variants of C1INH by examining their expression, function and intracellular location. The SP variants were transiently transfected into 293T cells. Their concentration was compared to WT C1INH. Functional analyses were performed by assessing their binding with C1s, kallikrein and FXIIa. Transfected HeLa cells were used to assess the intracellular localization of C1INH variants. Of 33 SP variants, six were poorly synthesized. Among these, three are in the H-region (L10R, L12R and L13-L15del) and three are in the C-region (G17R, A20D and S22L). Compared to WT, the remaining variants demonstrated normal recombinant protein expression and intact binding activity to their substrates. Protein aggregates were observed in the endoplasmic reticulum of L10R, G17R and S22L transfected cells. The H- and C-regions of SP are critical for C1INH production. Shortening or introducing positive charges into the hydrophobic core of the H-region can lead to pathogenic consequences. Disrupting the SP cleavage site in the C-region impairs protein production. This study provides new insights into the impact of SP variants on C1INH expression leading to HAE.
Neutrophils are the most abundant circulating leukocytes and are characterized by a proteome in which granule-associated proteins synthesized during granulopoiesis constitute a major fraction of total cellular protein, reflecting their preloaded effector nature in innate immune defense. A striking feature of neutrophil biology is the unusual abundance of the calcium-binding proteins S100A8 and S100A9, which together form the heterodimeric complex known as calprotectin. Early biochemical studies estimated that S100A8/A9 constitutes a substantial fraction of the soluble cytosolic proteome in neutrophils, with later studies often describing it as one of the most abundant protein complexes in these cells. Despite extensive studies on the antimicrobial and inflammatory activities of calprotectin, the biological rationale for this unusual abundance remains incompletely understood. In this review, we examine the structural, biochemical, and regulatory features of S100A8/A9 and explore the potential explanations for its high abundance in the neutrophil cytosol. We first discuss the unique organization of the neutrophil proteome and the transcriptional programs governing granulopoiesis that lead to large-scale production of neutrophil effector proteins. We then review the structural and biochemical properties of S100A8/A9, including its calcium-dependent conformational dynamics and high-affinity transition metal binding, which contribute to antimicrobial defense through nutritional immunity. Several functional hypotheses are considered to explain calprotectin abundance, including roles as an antimicrobial reservoir, a metal-sequestering molecule, a regulator of oxidative stress, and a source of damage-associated molecular patterns. Finally, we discuss the evolutionary logic of neutrophil protein preloading and the implications of calprotectin biology in inflammatory diseases and the tumor microenvironment. Resolving the abundance paradox of S100A8/A9 may reveal fundamental principles governing the organization of innate immune cell proteomes and provide new insights into the strategies used by neutrophils to achieve rapid and effective host defense.
Annular lichenoid dermatitis of youth (ALDY) is a rare lichenoid dermatosis characterized by distinctive clinical and histopathological features. Its etiopathogenesis remains poorly understood, and previously reported cases have consistently demonstrated polyclonal T-cell receptor (TCR) gene rearrangements. We report a patient with clinical, histopathological, and immunohistochemical findings consistent with ALDY in whom molecular analysis revealed monoclonal T-cell receptor rearrangement within the skin lesions. To our knowledge, this represents the first reported case of ALDY demonstrating T-cell monoclonality. This novel finding expands the current understanding of the molecular spectrum of ALDY and raises the possibility that cases with monoclonal T-cell rearrangement may represent a distinct clinicopathological variant. Based on our findings, we tentatively propose the term monoclonal annular lichenoid dermatitis of youth (MALDY) to describe this potential entity. Further studies are warranted to clarify its clinical significance and relationship to other cutaneous T-cell disorders.