Search Results (2,540)

Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4⁺/CD8⁺ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression. Full article

Ethanol is a pervasive chemical stressor in fermentative environments and represents a major ecological challenge for Drosophila melanogaster, a species that naturally inhabits decaying fruits. Although ethanol tolerance has traditionally been attributed to detoxification and antioxidant pathways, accumulating evidence indicates that immune-related genes, particularly those encoding immune deficiency (IMD) pathway-associated antimicrobial peptides (IMD-AMPs), contribute importantly to chemical stress adaptation. Previous studies have demonstrated that IMD-AMP induction is required for ethanol tolerance; however, whether elevated IMD-AMP expression alone is sufficient to enhance tolerance has remained unresolved. In this study, we investigated the functional significance of IMD-AMP upregulation in ethanol tolerance using dietary propolis as an experimental immune-modulating agent. D. melanogaster were reared throughout their life cycle on propolis-supplemented diets and subsequently exposed to ethanol. Propolis-fed flies exhibited significantly enhanced survival under ethanol stress compared with control flies. Notably, this increased tolerance was not accompanied by upregulation of classical ethanol metabolism genes or broad induction of antioxidant-related genes. Instead, propolis feeding increased baseline and early-stage expression of IMD-AMP genes, including Diptericin A (DptA), Diptericin B (DptB), Attacin (AttC), and Metchnikowin (Mtk) before and during ethanol exposure. These findings suggest IMD-AMP upregulation is positively associated with enhanced ethanol tolerance in D. melanogaster. Our results establish a proactive role for immune-related pathways in chemical stress resistance and extend the functional scope of AMPs beyond pathogen defense. This study identifies IMD-AMPs as key effectors linking immune activation to physiological adaptation under ethanol-induced chemical stress. Full article

SIRT2 (Sirtuin 2) is an NAD+-dependent deacetylase that exerts crucial regulatory effects on immune homeostasis and macrophage activation. While chronic cold exposure is a known predisposing factor for pulmonary dysfunction, the precise mechanisms by which SIRT2 potentially modulates lung macrophage polarization under cold stress remains poorly understood. In this study, we evaluated the protective capacity of SIRT2 using both wild-type (WT) and Sirt2-knockout (Sirt2−/−) murine models subjected to chronic cold exposure (4 °C for 3 h daily over 21 days). Our results demonstrated that Sirt2 deficiency significantly exacerbated cold-induced pulmonary histopathological damage and increased the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) (p < 0.05). Furthermore, chronic cold stress triggered a macrophage-centered inflammatory response, a process wherein SIRT2 was found to curtail M1 pro-inflammatory polarization. To further investigate these mechanisms, in vitro experiments were conducted using the mouse alveolar macrophage cell line MH-S. While LPS was utilized as a canonical inflammatory stimulus to mimic the injury environment, SIRT2 overexpression was found to reverse the LPS-induced increase in M1 markers and attenuate inflammatory cytokine secretion. These findings suggest that SIRT2 maintains intracellular homeostasis by modulating macrophage plasticity and plays a protective role in the development of chronic cold stimulus-induced lung injury. Consequently, SIRT2 activation may represent a potential therapeutic pathway for the treatment of environment-related respiratory diseases. Full article

Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder with important genetic, endocrine, immune, and metabolic determinants. Growing evidence links vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms to pregnancy complications, including RPL. A narrative review was conducted via a literature search in major databases: PubMed, EMBASE, Scopus, and Web of Science from January 2010 to January 2026, which synthesized observational studies on maternal 25-hydroxyvitamin D [25(OH)D] status and/or VDR polymorphisms in RPL, with predefined eligibility criteria and qualitative risk-of-bias assessment. Most studies focused on FokI (rs2228570) and the 3′ regulatory block BsmI/ApaI/TaqI. FokI is the most extensively studied VDR variant in RPL and showed the most consistent directional association compared with other variants, particularly in Asian and Middle Eastern populations, though the effect varied by study design, ancestry, and covariate adjustment. Contrary to that, investigations of BsmI/ApaI/TaqI loci were not consistent due to ancestry-specific linkage disequilibrium (LD). Genotype and vitamin D interaction effects were scarcely studied, with stratified analyses indicating a more significant genotype effect under vitamin D deficiency. From clinical practice perspectives, VDR polymorphisms may explain why some patients with RPL have a poor response to standard vitamin D supplementation. Women with the FokI f allele polymorphism associated with lower VDR activity require higher vitamin D dosing or earlier immunomodulatory support to achieve adequate endometrial receptivity. VDR variation, particularly FokI, may contribute to RPL susceptibility within an endocrine–immune–metabolic framework. Clinical translation will require standardized RPL definitions, concurrent 25(OH)D assessment, robust control for confounders, and analytical models that account for gene–environment interactions. Full article

Background/Objectives: CTLA-4 is a key checkpoint of peripheral immune regulation, yet its biology cannot be reduced to inhibitory signaling alone. This review discusses CTLA-4 as a dynamic regulatory pathway shaped by ligand handling, intracellular trafficking, recycling, and cell-type-specific function, and examines how these features link molecular mechanism to human disease and therapy. Methods: We synthesized the structural, mechanistic, translational, and clinical literature spanning CTLA-4 molecular biology, cell-type-specific function, inborn errors of immunity, polygenic autoimmunity, transplantation, cancer immunotherapy, and immune-related adverse events. Results: CTLA-4 function depends on surface availability, trans-endocytosis of CD80/CD86, and tight control of endosomal trafficking. These features help explain why CTLA-4 haploinsufficiency, LRBA deficiency, and DEF6 deficiency converge clinically despite different upstream lesions, and why subtler CTLA-4 variation contributes to polygenic autoimmunity. Therapeutic studies also provide mechanistic insight. Abatacept can partly replace pathway function in monogenic disease, whereas belatacept highlights the limits of ligand blockade when endogenous coinhibition is also lost. In oncology, anti-CTLA-4 antibodies act through a more complex interplay involving checkpoint blockade, Fc biology, intratumoral Treg depletion, and receptor recycling. Emerging next-generation agents aim to retain antitumor activity while reducing systemic toxicity through more selective use of these mechanisms. Conclusions: Rather than a static inhibitory receptor, CTLA-4 is better viewed as a context-dependent regulatory pathway whose function depends on trafficking, surface availability, and cellular context. This perspective links molecular mechanism to clinical phenotype and supports more precise CTLA-4-targeted therapy. Full article

Background: Food protein-induced allergic proctocolitis (FPIAP) is generally considered a benign and self-limited condition; however, both its natural course and the impact of management strategies on prognosis remain controversial. Data on modifiable factors influencing tolerance acquisition are limited. Methods: We conducted a retrospective cohort study including 180 infants with cow’s milk-induced FPIAP. Clinical characteristics, management strategies, and outcomes were analysed. Logistic regression was used to identify factors associated with delayed tolerance, and Kaplan–Meier and Cox regression analyses were performed to evaluate time to tolerance. Results: Tolerance was achieved in 91.2% of infants, with a median time from diagnosis to tolerance of 31.1 weeks. In multivariable logistic regression, multi-food elimination at presentation (OR, 2.58; 95% CI, 1.02–6.54; p = 0.046) and a longer interval from diagnosis to reintroduction (OR per week, 1.08; 95% CI, 1.02–1.14; p = 0.022) were independently associated with delayed tolerance. Exclusive breastfeeding was associated with lower odds of delayed tolerance in univariable analysis but not after adjustment. In unadjusted time-to-event analyses, observation-first management was associated with earlier tolerance acquisition (HR, 0.37; 95% CI, 0.22–0.62; p < 0.001), whereas multiple food allergy was associated with a lower probability of tolerance acquisition over time (HR, 0.60; 95% CI, 0.41–0.88; p = 0.009). Feeding modality also showed an unadjusted temporal association with tolerance acquisition, with exclusively breastfed infants demonstrating a more favorable pattern than formula-fed infants. Conclusions: The course of FPIAP appears to be influenced not only by clinical characteristics but also by management strategies. Delayed reintroduction and multi-food elimination were associated with later tolerance, while observation-first management was associated with earlier tolerance acquisition. These findings suggest that commonly used strategies such as prolonged elimination or delayed reintroduction may warrant reconsideration in selected infants and support a more individualized and less restrictive approach to management. Full article

Background: Pregnancy presents unique immunological and obstetrical challenges for women with Common Variable Immune Deficiency (CVID). No standardized guidelines currently exist to guide pregnancy management, as CVID is a rare diagnosis, with pregnancy outcomes limited to case reports and case series. Establishing a structured approach to care is important to optimize maternal and fetal outcomes. Methods: A narrative review of the literature with a structured search was performed to detail pregnancy outcomes in CVID and management strategies. A 10-year retrospective chart review of women with CVID who became pregnant while receiving care at the McGill University Health Centre between January 2015 and January 2025 was conducted to add to the existing clinical data. Results: Pregnancy outcomes were improved through pre-conception planning, regular serum Immunoglobulin G (IgG) monitoring, trimester-based immunoglobulin replacement dose adjustments, proactive management of autoimmune or infectious complications, and multidisciplinary care. Subcutaneous immunoglobulin may offer better flexibility and stability of IgG levels. Conclusions: In the available observational literature and our institutional experience, many patients with CVID have carried pregnancies to term with favorable maternal and neonatal outcomes when managed with IgRT and multidisciplinary coordination. We outline a stepwise multidisciplinary framework for clinicians caring for women with CVID who are planning or undergoing pregnancy, and we identify gaps in knowledge for future studies. Full article

Vitamin D has been implicated in immune modulation and susceptibility to respiratory infections, including COVID-19. However, data in asymptomatic pediatric populations, particularly those with household exposure, remain limited. This study aimed to investigate the association between serum vitamin D levels and hematological parameters with SARS-CoV-2 PCR positivity in asymptomatic children, and to evaluate their potential role in early risk stratification. This retrospective study included 127 asymptomatic children (aged 2–18 years) with confirmed household exposure to COVID-19. Participants were classified as PCR-positive (n = 74) or PCR-negative (n = 53). Serum 25(OH)D3 levels and hematological parameters were analyzed. Univariate and multivariable logistic regression analyses were performed to identify independent predictors. Receiver operating characteristic (ROC) curve analysis was used to assess discriminative performance, and a combined multimarker model was constructed. Serum vitamin D levels were significantly lower in PCR-positive children compared to PCR-negative children (17 ± 8 vs. 27 ± 11 ng/mL, p = 0.001). White blood cell (p = 0.002), platelet (p = 0.01), and neutrophil counts (p = 0.01) were significantly reduced, while basophil counts were higher in PCR-positive children (p = 0.02). In multivariable analysis, vitamin D (OR: 0.87, 95% CI: 0.82–0.93, p < 0.001), platelet (p = 0.02), neutrophil (p = 0.02), and basophil counts (p = 0.01) remained independent predictors. ROC analysis showed that vitamin D had moderate discriminative performance (AUC: 0.75, 95% CI: 0.67–0.83), while platelet (AUC: 0.64), neutrophil (AUC: 0.61), and basophil (AUC: 0.62) counts showed modest performance. The combined multimarker model demonstrated improved predictive ability (AUC: 0.80, 95% CI: 0.72–0.88), with sensitivity of 71.6% and specificity of 68.2%. Additionally, vitamin D deficiency was significantly more frequent in PCR-positive children (43% vs. 19%, p = 0.003). Conclusions: Lower vitamin D levels and associated hematological alterations are independently associated with SARS-CoV-2 PCR positivity in asymptomatic children. A combined biomarker approach may improve early risk stratification using simple and routinely available parameters. Further prospective studies are needed to validate these findings and clarify the role of vitamin D in preventive strategies. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) comprises biologically heterogeneous tumors, primarily lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which differ in genomic landscape and clinical behavior. The tumor suppressor PTEN is a key negative regulator of the PI3K/AKT/mTOR pathway and is frequently inactivated in NSCLC through genetic and non-genetic mechanisms. Although reduced PTEN expression has been associated with poor outcomes in lung cancer, its prognostic relevance across these histological subtypes remains unclear. Methods: Here, we investigated the prognostic significance of PTEN in NSCLC subtypes using a multi-level approach combining protein, transcriptomic, and genomic analyses. PTEN protein expression was evaluated by immunohistochemistry in a tissue microarray from resected NSCLC patients, and findings were validated using publicly available datasets including TCGA-RPPA, GEO/EGA-based transcriptomic cohorts, and large genomic resources. In parallel, mutational landscapes and co-mutation patterns were analyzed in several independent datasets, and tumor immune microenvironment composition was inferred using CIBERSORT deconvolution analysis. Results: Low PTEN protein and mRNA levels, as well as PTEN mutations, were consistently associated with significantly worse overall survival (OS) in LUAD but not in LUSC. Multivariable Cox regression analysis confirmed PTEN as an independent prognostic factor in LUAD. Although PTEN mutations were more frequent in LUSC, they showed no prognostic value in this subtype. Co-mutation analyses revealed recurrent PTEN partnerships with TP53, EGFR, and APC in LUAD, with PTEN-TP53 co-alterations enriched in metastatic disease. Immune deconvolution demonstrated that PTEN-low LUAD tumors were characterized by an immunosuppressive microenvironment, including increased T regulatory cells and reduced inflammatory immune populations. Notably, increased M2-like macrophages were associated with shorter OS in PTEN-low LUADs, whereas a high number of total macrophages (CD68+ cells) emerged as an independent predictor of more favorable OS. Conclusions: Collectively, these results identify PTEN loss as a subtype-specific prognostic biomarker in LUAD and link its deficiency to immunosuppressive tumor microenvironment remodeling. Full article

Transthyretin (TTR) amyloidosis is a systemic, progressive, and fatal disease. TTR is integral in vitamin A (retinol) transport via its binding to retinol binding protein 4 (RBP4). Current and emerging therapies for TTR amyloid cardiomyopathy (ATTR-CM), including RNAi therapies and potentially CRISPR-based therapies, reduce hepatic transthyretin production and hence decrease serum RBP4, which decreases circulating vitamin A levels. However, despite these reductions in circulating vitamin A, hepatic reserves and alternative delivery mechanisms may prevent clinical manifestations of vitamin A deficiency. Vitamin A functions as a key regulator of immunity, antioxidant function, cell growth and differentiation and vision. This paper aims to serve as a comprehensive review of vitamin A and its metabolites, their transport, and their function in human health and disease. Additionally, we seek to synthesize the relevant outcomes and safety data of TTR silencing therapies and how they relate to circulating vitamin A levels and vitamin A-related clinical outcomes in a manner that is relevant to the cardiac amyloidosis specialist. Full article

GATA2 deficiency predisposes patients to recurrent infections, myelodysplastic neoplasms (MDSs), and malignancies through disrupted hematopoiesis and immune dysfunction. The role of the gut microbiome (GM) in this condition remains poorly defined. In this multicenter study, we analyzed GM composition, metabolomic, and lipidomic profiles in 12 Italian GATA2-deficient patients, comparing non-HSCT and post-HSCT GATA2-deficient individuals with healthy controls. Non-HSCT patients showed a relative enrichment of Proteobacteria-associated Gram-negative taxa, accompanied by increased levels of metabolites and lipids previously associated with inflammatory processes. Post-HSCT patients displayed profiles with a trend toward partial normalization of GM composition and metabolic features. Overall, our findings suggest the presence of microbiome and metabolic patterns in GATA2-deficient patients, which may reflect underlying immune and hematopoietic alterations, although these observations should be interpreted as descriptive and require validation in larger cohorts. Full article

Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality. Its molecular pathogenesis, especially systemic immune dysregulation, remains unclear. Public transcriptomic datasets underwent machine learning to identify biomarkers, which were validated in external cohorts and single-cell RNA-seq. In vitro and ex vivo validations included: qRT-PCR and ELISA in CSE/LPS-stimulated macrophages to assess drug efficacy (Celecoxib/Lovastatin); RORC overexpression; Western blotting in patient-derived primary T cells and TCF7-deficient Jurkat cells with genetic rescue; and immunofluorescence of human lungs. A three-gene signature (RORC, TCF7, and CLEC4D) consistently discriminated COPD. CLEC4D localized to myeloid cells, while RORC/TCF7 mapped to lymphoid lineages. Celecoxib and Lovastatin attenuated macrophage inflammation, partially via RORC preservation. Crucially, the TCF7 protein was depleted in COPD primary T cells. TCF7 knockdown downregulated pro-caspase-8, which was fully reversed by TCF7 re-expression. Immunofluorescence confirmed disrupted TCF7/caspase-8 spatial patterns in COPD lungs. This signature highlights innate hyperactivation and adaptive T-cell alterations in COPD, providing novel mechanistic insights into immune dysregulation and potential pharmacological targets. Full article

Grade C molar-incisor pattern periodontitis (C-MIP) is a rapidly progressive form of periodontal disease affecting young individuals that is often linked to a highly virulent genotype of Aggregatibacter actinomycetemcomitans (Aa). Although Aa is present in the healthy oral microbiome, its transition into subgingival tissue correlates with the conversion from healthy to diseased status within the periodontal pocket. These changes may be due to immune evasion strategies attributed to Aa exotoxins. We previously demonstrated that a host cell protein, cellugyrin, plays a critical role in exotoxin internalization and subsequent cytotoxicity. Herein, we assess the contribution of cellugyrin to Aa phagocytosis and intracellular trafficking in human macrophages. Confocal imaging demonstrated that Aa co-localizes with cellugyrin. Importantly, cellugyrin-deficient macrophages exhibited a significant reduction in phagocytosed Aa. Furthermore, we analyzed the role of retrograde trafficking in Aa survival. Retro-2-mediated inhibition of this trafficking pathway resulted in increased intracellular Aa, likely due to increased survival. Collectively, our findings suggest that cellugyrin is involved in Aa phagocytosis and that retrograde trafficking may play a role in subsequent host cell clearance of Aa. Full article

Background/Objectives: Heart transplant recipients are particularly at risk for micronutrient deficiencies due to chronic immunosuppression, metabolic disorders, gastrointestinal absorption disorders, and increased postoperative demand. Despite a growing body of evidence suggesting their clinical relevance, the prevalence, characteristics, and consequences of these deficiencies remain poorly defined. The aim of this review was to assess of selected micronutrient deficiencies in personnel after heart vaccination and risk factors for their control. Methods: This scoping review was conducted in accordance with the Joanna Briggs Institute’s scope review methodology and presented in accordance with the PRISMA-ScR guidelines. A systematic search of PubMed, Scopus, EBSCO, Web of Science, Google Scholar, and Cochrane Library (January–February 2026) identified studies assessing micronutrient deficiencies in adult heart transplant recipients. Original publications, meta-analyses, and reviews available in full text in English were eligible for the review. Data extraction was carried out independently by two reviewers; using the PCC (Population–Concept–Context) model. Results: Of the 35 pre-identified records, 12 studies met the inclusion criteria. The most commonly reported deficiencies included iron, vitamin D, and B vitamins, and their incidence varied widely due to heterogeneous diagnostic criteria. Iron deficiency—both absolute and functional—was common and often associated with inflammation and impaired hepcidin regulation. Vitamin D deficiency persisted before and after transplantation and was associated with impaired bone health, inflammation, and a potentially increased risk of infection. Elevated homocysteine levels associated with low levels of folic acid and vitamin B6 have been identified as potential contributing factors to atherosclerotic and thrombotic complications. Limited evidence also points to deficiencies in iodine, zinc, and other trace elements. Conclusions: Micronutrient deficiencies are common among heart transplant recipients and can adversely affect immune system function, cardiovascular risk, and overall clinical outcomes. Routine evaluation and targeted correction of deficiencies should be considered in post-transplant care. Further prospective, multicenter, and interventional studies are needed to establish standardized diagnostic criteria and evidence-based supplementation strategies. Full article

Phospholipid fatty acid incorporation and remodeling are central processes through which immune cells adapt their membranes during activation. Macrophages are known to integrate oxidized fatty acids into phospholipids, yet the principles governing this distribution remain incompletely defined. Hydroxyeicosatetraenoic acids (HETEs) are abundant products generated during inflammation, and their integration into membrane phospholipids may influence signaling, trafficking, and membrane organization. Although individual HETE isomers differ in biosynthesis and function, it is not known whether macrophages handle them differently. Here, we address how 5-, 12-, and 15-HETE are incorporated into murine peritoneal macrophage phospholipids during inflammatory stimulation. We show that each isomer exhibits a distinctive phospholipid-class distribution, with 12-HETE preferentially entering choline phospholipids (PC), 15-HETE enriching phosphatidylinositol (PI), and 5-HETE distributing more broadly across PC, PI and ethanolamine phospholipids (PE). All three isomers are incorporated predominantly at the sn-2 position and showed similar molecular species distribution within each class, with diacyl PC, PE plasmalogens, and PI(18:0/HETE) serving as dominant acceptors. RAW264.7 cells reproduce these patterns. In ether phospholipid-deficient RAW.108 cells, incorporation into ether species is lost but compensated by increased routing into diacyl PC and PE, while PI incorporation remains unchanged. Collectively, these findings reveal that phospholipid class, not simple availability, determines where HETEs are incorporated. This distribution is preserved across macrophage cell types and remains intact even when ether phospholipids are absent, indicating that class specific pathways, rather than lipid subclass composition, primarily determine HETE incorporation. Full article