Search Results (871)

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease, predominantly affecting elderly patients with multiple comorbidities. This multicentre retrospective cohort study aimed to characterize the clinical profile, treatment patterns, and drug-associated cases of BP in a real-world setting. The study included 156 patients newly diagnosed with BP between 2020 and 2024 in four dermatology departments in Poland. Diagnosis was based on clinical features, and immunological assessment, including direct immunofluorescence (DIF), ELISA, and BIOCHIP-based indirect immunofluorescence. The mean age at diagnosis was 75.5 ± 10.9 years, and 78.85% of patients had at least one comorbidity, most commonly arterial hypertension, type 2 diabetes mellitus, and dyslipidemia. Severe pruritus was reported in 74.14% of evaluated patients. Blisters and erosions were the predominant clinical manifestations. Topical glucocorticosteroids were the most frequently used treatment, followed by systemic glucocorticosteroids and methotrexate. New drug exposure within 6 months before disease onset was identified in 14.74% of patients and was associated with a shorter time to diagnosis. Drug-associated cases showed lower BP180 ELISA positivity, although this did not remain significant after correction for multiple testing. These findings highlight the clinical complexity of BP and the importance of medication review and direct immunofluorescence in diagnostic evaluation. Full article

Per- and polyfluoroalkyl substances (PFAS) are persistent, chemically stable compounds widely used in daily life. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS) were identified as the most relevant PFAS due to their prevalence and toxicity. This study aimed to investigate the immunotoxic mechanisms of a mixture of these PFAS using an in silico approach. Comparative Toxicogenomic Database (CTD), GeneMANIA, CytoHubba (Cytoscape), ToppGene Suite, and Metascape were used for the analysis. A total of 65 immune-related genes were identified as common to all four PFAS, with IFNG, TNF, IL1B, IL6, TYK2, CD3E, CASP8, VAV1, ARHGAP4, and CARD11 emerging as key hub genes. CTD phenotype analysis indicated immune dysregulation, with decreased humoral and adaptive immune responses in humans and tissue-specific modulation of B- and T-cell activity in mice, while no immune-related phenotypes were observed for PFNA. Network analysis identified functional modules associated with apoptotic and immune signaling, endothelial cell migration and angiogenesis, and shared inflammatory and viral response pathways. Disease enrichment analysis associated PFAS with autoimmune disorders (rheumatoid arthritis, asthma), metabolic conditions, and cardiovascular diseases (experimental diabetes, hypertensive disease). These results highlight PFAS involvement in immune modulation, cytokine signaling, and disease susceptibility. Full article

Background and Objectives: Autoimmune thyroiditis (AIT) is often reported patients with PCOS, and may co-occur with altered metabolic risk markers. The aims of this study were to assess baseline differences according to thyroid autoimmunity status, evaluate adjusted associations between thyroid autoimmunity and metabolic parameters, examine associations with PCOS phenotype distribution, and perform k-means clustering to explore data-driven subgroups and their autoimmune enrichment. Materials and Methods: We performed a retrospective cohort study of 651 women with PCOS, comparing those without AIT (n = 506) versus with AIT (n = 145). Associations between AIT and continuous outcomes (HDL; composite metabolic score) were evaluated using robust linear regression with HC3 standard errors and age modeled with a natural cubic spline (3 knots). The association between AIT and phenotype A was assessed via logistic regression with exponentiated coefficients (odds ratios). Unsupervised phenotyping used k-means clustering with silhouette analysis across k = 2…6. Results: Patients with AIT were older (median 40 vs. 35 years; p = 0.021). Phenotype distribution differed by AIT status (overall p = 0.029), with phenotype A less frequent among AIT-positive women (27% vs. 40%). In adjusted robust regression, AIT was associated with lower HDL by β = −4.34 mg/dL (95% CI −9.18 to 0.51; p = 0.081), while obesity (−7.04 mg/dL; p < 0.001) and diabetes (−6.47 mg/dL; p = 0.004) were associated with lower HDL. AIT was not associated with the composite metabolic score (β = −0.005; 95% CI −1.22 to 1.21; p = 0.994), whereas obesity was associated with higher score (β = 1.76; p = 0.003) and urban residence with lower score (β = −0.94; p = 0.011). In logistic regression, AIT was associated with lower odds of phenotype A (OR 0.63; 95% CI 0.41–0.97; p = 0.038), and hypertension was associated with higher odds of phenotype A (OR 1.91; 95% CI 1.20–3.04; p = 0.006). Silhouette analysis supported k=3 clusters (silhouette 0.349), and AIT prevalence was highest in cluster 3 (26.4%) versus clusters 1 (19.9%) and 2 (18.3%). Conclusions: AIT was associated with lower odds of phenotype A, and showed a borderline association with lower HDL-cholesterol but not with a composite metabolic score. Data-driven clustering identified a subgroup with higher autoimmune burden. Full article

Background and Objectives: Neurological complications of SARS-CoV-2 infection frequently impair patients’ long-term quality of life. This study aimed to identify clinical and laboratory risk factors—including inflammatory markers and micronutrients—for the occurrence or worsening of neurocognitive disorders in long COVID patients. Materials and Methods: In this prospective observational study, patients presenting with long COVID neurological manifestations were stratified by baseline MoCA score into two groups (≥23 and <23). Clinical, laboratory (inflammatory markers, 25-hydroxy vitamin D, vitamin B12, folic acid), and neuroimaging assessments (global cortical atrophy scale, Fazekas score) were performed over 24 months. Propensity score matching (PSM) for age, gender, and neurological comorbidities yielded 54 patients per group. Results: In the MoCA ≥ 23 group, significant predictors of cognitive decline included severe COVID-19 (OR = 2.211, 95% CI = 1.819–5.973, p = 0.012), autoimmune comorbidities (OR = 1.676, 95% CI = 1.191–2.390, p = 0.043), and elevated neutrophil-to-lymphocyte ratio (NLR; OR = 1.586, 95% CI = 1.431–2.122, p = 0.011). In the MoCA < 23 group, independent predictors were diabetes mellitus (OR = 3.021, 95% CI = 2.65–14.004, p = 0.016), autoimmune comorbidities (OR = 4.987, 95% CI = 1.412–6.033, p = 0.021), and NLR (OR = 5.944, 95% CI = 2.353–19.321, p = 0.015). Serum vitamin D levels were significantly associated with MoCA scores in both groups. Conclusions: COVID-19 severity, autoimmune comorbidities, NLR, and serum vitamin D represent key risk factors for neurocognitive decline in long COVID, highlighting potential targets for early intervention. Full article

The global prevalence of autoimmune diseases ranges from 3% to 8%, with women at a significantly higher risk than men. The core mechanisms underlying these diseases include impaired T-cell and B-cell immune tolerance, abnormal cytokine production, and aberrant activation of related signaling pathways. Conventional treatments primarily focus on suppressing immune responses, but their efficacy remains limited and they are often associated with substantial side effects. Nanomedicine leverages nanoscale materials to enable precise diagnosis and targeted therapy. Nanocarriers can penetrate biological barriers, enhance cellular uptake, and prolong circulation time in vivo, demonstrating considerable potential for drug delivery. Common nanoscale drug delivery platforms include nanoparticles, polymeric micelles, liposomes, dendrimers, mesoporous materials, hydrogels, and exosomes. Each carrier type possesses distinct characteristics in terms of drug-loading capacity, stability, responsiveness, and biocompatibility, thereby enabling targeted delivery and controlled release. This review summarizes recent advances in nano-delivery technologies for three representative chronic autoimmune diseases: diabetes mellitus (DM), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA). Nano-delivery systems can improve therapeutic outcomes by optimizing drug delivery, targeting complications, and modulating the pathological microenvironment. They enhance drug bioavailability, reduce off-target and systemic adverse effects, and provide novel strategies for the precise and efficient treatment of chronic autoimmune diseases. Full article

Down syndrome (DS), caused by trisomy 21, is associated with a wide spectrum of endocrine and gastrointestinal disorders that often arise early in life and significantly impact long-term health. This narrative review examines the pathophysiological mechanisms underlying these conditions, with a particular focus on their bidirectional interactions. Endocrine abnormalities in DS, including thyroid dysfunction, type 1 diabetes mellitus, growth impairment, and altered bone metabolism, occur at higher rates than in the general population and are largely driven by immune dysregulation, chronic inflammation, and gene dosage effects. Similarly, gastrointestinal disorders—ranging from congenital malformations to autoimmune conditions such as celiac disease—are highly prevalent and often present with atypical clinical features. Emerging evidence highlights the central role of gut dysbiosis, characterized by reduced microbial diversity and increased pro-inflammatory taxa, in modulating immune and metabolic pathways. This altered gut environment contributes to a chronic inflammatory state and may promote autoimmunity and endocrine dysfunction through the gut–endocrine–immune axis. Nutritional deficiencies and epigenetic factors, including microRNA dysregulation, further influence disease expression. Understanding this complex cross-talk is essential for improving clinical management. Integrated, multidisciplinary approaches and early screening strategies are crucial to optimize outcomes and guide future research in DS. Full article

Type 1 Diabetes (T1D) is a complex autoimmune disorder characterized by immune-mediated destruction of pancreatic β cells, driven by genetic susceptibility and modulated by environmental factors, notably the gut microbiome. Dysbiosis, manifested as reduced microbial diversity, perturbations in the Firmicutes/Bacteroidetes ratio, and compromised short-chain fatty acid production, contributes to T1D pathogenesis through mechanisms involving immune system dysregulation and heightened intestinal permeability. Emerging evidence indicates a relationship between the gut and oral microbiomes, as well as the potential influence of the virome and mycobiome. This narrative review synthesizes the current literature on the intricate interplay between the gut microbial ecosystem, the host immune response, and the development of T1D, highlighting the potential for targeted microbiome-based interventions to ameliorate disease progression. A more nuanced understanding of these multi-kingdom interactions is essential for developing precise therapeutic strategies to prevent or delay T1D onset and to improve patient outcomes through restoration of immune tolerance and gut homeostasis. Full article

Background/Objectives: DNAJC3-related syndromic monogenic diabetes is a rare autosomal recessive disorder that presents as juvenile-onset non-autoimmune diabetes; it has been associated with sensorineural hearing loss, hypothyroidism, short stature, and variable degrees of neurological manifestations. A delayed diagnosis occurs frequently because of fragmented subspecialty care and lack of awareness of syndromic monogenic diabetes. Methods: We report a 34-year-old Saudi male from a consanguineous family with insulin-treated diabetes diagnosed during adolescence. He had long-standing sensorineural hearing loss, hypothyroidism, and short stature, which were managed separately. Results: Genetic analysis using whole-exome sequencing identified a homozygous likely pathogenic DNAJC3 variant, c.1177C>T p.(Arg393*), confirming the diagnosis of DNAJC3-related syndromic monogenic diabetes. In addition, he demonstrated no clinically evident neurological manifestations at the time of evaluation, including ataxia, despite reaching adulthood, highlighting the phenotypic variability associated with DNAJC3-related disease. Conclusions: This case adds to the growing evidence supporting phenotypic variability in DNAJC3-related syndromic monogenic diabetes by describing an adult presentation without clinically evident neurological manifestations at the time of evaluation. It highlights how systemic manifestations may remain unrecognized when managed separately across different specialties. In individuals with atypical diabetes accompanied by multisystem involvement, particularly in the setting of consanguinity, early consideration of monogenic diabetes and timely genetic testing may facilitate accurate diagnosis and molecular classification. Establishing a specific genetic diagnosis supports appropriate genetic counseling, informs reproductive decision-making, and may help reduce prolonged diagnostic uncertainty. Full article

Latent autoimmune diabetes in adults (LADA) is a form of diabetes with clinical and biological features overlapping those of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), which may complicate early diagnosis and disease classification. Interest in proteomic and related biomarker profiles in LADA has increased in recent years because these markers may improve understanding of its pathophysiology and support more accurate differentiation from other forms of diabetes. This narrative review provides a structured overview of currently available evidence on selected inflammatory, immunological, and metabolic biomarkers associated with LADA. The reviewed literature includes data on adiponectin, IFN-γ, CCL2/MCP-1, IL-6, GPLD1, and other markers potentially linked to immune dysregulation, low-grade inflammation, and progressive β-cell dysfunction. Several studies suggest that LADA may present an intermediate biomarker profile, with some features overlapping with T1DM and others with T2DM. At the same time, the available evidence remains heterogeneous and is limited mainly by small sample sizes, cross-sectional designs, and incomplete clinical validation. Therefore, although several biomarkers appear promising for further investigation, their current role should be regarded as exploratory rather than established for routine clinical use. Further longitudinal and well-characterized studies are needed to determine whether selected biomarker patterns may eventually contribute to improved identification and stratification of LADA. Full article

Background/Objective: Type 1 diabetes (T1D) is a complex autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells. The TAB2/SUMO4 locus has been implicated in T1D susceptibility through a biochemical mechanism involving NFκB. Given that alterations in NFκB activity have been linked to the etiology of T1D, this study evaluated the association between single nucleotide polymorphisms (SNPs) in the TAB2/SUMO4 region (rs6942381, rs237027, rs237025, and rs7896) and T1D in a population from southern Brazil. Methods: Two T1D groups, each comprising 150 with childhood-onset (aged ≤14 years) and 150 with adulthood-onset (aged >18 years) were compared with healthy controls (165 children aged ≤14 years and 150 adults aged >18 years, respectively). Genotyping of SNPs in the TAB2/SUMO4 region was performed using real-time PCR. Results: All polymorphisms were in Hardy–Weinberg equilibrium. The genotype and allele frequencies of the studied polymorphisms in the TAB2/SUMO4 region did not differ among groups in either children or adults. The MAF of the children and adults controls are respectively for rs6942381 49.1% (95% CI 44–54%) and 48.0% (95% CI 42–52%), rs237027 12.4% (95% CI 9–16%) and 11.7% (95% CI 8–15%), rs237025 45.5% (95% CI 40–51%) and 46.0% (95% CI 41–52%) and rs7896 18.2% (95% CI 14–22%) and 24.3% (95% CI 19–29%). The haplotype frequencies were also similar between groups. The observed minor allele frequencies were similar to those reported in European populations. Conclusions: TAB2/SUMO4 locus polymorphisms (rs6942381, rs237027, rs237025, and rs7896) were not associated with childhood- or adulthood-onset T1D in the studied population. Full article

Type 1 diabetes is caused by autoimmune destruction of insulin-secreting β-cells within islets of Langerhans. Transplantation of donor islets can improve glycaemic control, but current clinical islet transplantation protocols are compromised by extensive loss of β-cell functional mass soon after implantation. Co-incubation in vitro or co-transplantation in vivo of mesenchymal stromal cells (MSCs) with isolated islets improves their functional survival, although the underlying mechanisms remain obscure. Here, we show that MSC-derived extracellular vesicles (MSC-EVs) are alone sufficient to recapitulate many of the beneficial effects of MSCs on islet functional survival, offering the possibility of simple cell-free treatments to improve the outcomes of islet transplantation. We used LC- analysis and small RNA sequencing to analyse the protein and microRNA (miRNA) molecular cargos of MSC-EVs. Proteomic analysis identified >100 proteins from the Uniprot Mouse Database, including β-cell G protein-coupled receptor (GPCR) agonists which we have previously shown to enhance β-cell functional survival. MSC-EVs contained ~300 distinct miRNAs and we identified five highly enriched miRNAs that were significantly upregulated in MSC-EV-treated islets, notably miR-21a-5p. MSC-EV treatment also altered the expression of a distinct set of islet mRNAs known to be involved in islet metabolism and function. These observations may enable the further simplification of the islet pretreatment strategy by focusing on defined GMP-grade biologically active molecules rather than whole heterogeneous EV populations. Full article

Type 1 diabetes (T1D) is driven by autoreactive CD4⁺ T-cell responses to pancreatic beta cell antigens presented by disease-associated human leucocyte antigen (HLA) class II molecules. However, the molecular mechanisms by which subtle antigenic modifications promote pathogenic immunity remain incompletely defined. Recent immunopeptidomic studies have identified a cysteine-to-serine substitution at position 19 of the insulin B chain, referred to as InsC19S, as a microenvironment-driven neoepitope that can be presented by HLA class II molecules, including HLA-DQ8, and is recognized by diabetogenic CD4⁺ T cells. In this study we explore potential structural and thermodynamic mechanisms that may contribute to the enhanced immunogenicity associated with this single-amino-acid modification. Using molecular dynamics simulations combined with coarse-grained free-energy-perturbation analyses, we compared HLA DQ8 complexes bound to wild-type (WT) insulin and InsC19S peptides. The InsC19S variant is predicted in simulations to exhibit enhanced binding stability, characterized by increased hydrogen bond occupancy, reduced peptide conformational mobility, and a more favorable binding free energy. In addition, the modified peptide is predicted to induce peptide-dependent conformational adjustments within the HLA-DQ8 peptide-binding groove, resulting in expansion of the conformational landscape and stabilization of distinct low-energy states that are not accessed by the WT complex. Principal component analysis and free-energy landscape mapping suggest that this mutation may promote altered collective motions within HLA DQ8 that are consistent with enhanced peptide major histocompatibility complex (MHC) persistence and optimized antigen presentation geometry. Together, these computational observations suggest a structural framework that may help explain the preferential presentation and pathogenic recognition of InsC19S reported in experimental studies. These findings provide a molecular-level framework that may help link microenvironment-driven insulin neoepitope formation to altered peptide–MHC stability and conformational dynamics in HLA-DQ8. Full article

The gut microbiota is increasingly recognized as an important factor in the pathogenesis of type 1 diabetes (T1D), although its exact role in disease initiation and progression remains uncertain. Earlier interpretations considered alterations in intestinal microbial composition as secondary effects of immune dysregulation or metabolic disturbance. Recent longitudinal studies, however, suggest that specific microbial changes occur before the onset of islet autoimmunity, indicating a potential contributory role in the early phases of disease development. In this narrative review article, the gut–pancreas axis (GPA) is described as a dynamic and reciprocal system in which microbial, metabolic, and immune processes influence each other to shape β-cell outcomes. Evidence from human cohorts and experimental models links early life reductions in microbial diversity, impaired intestinal barrier function, and decreased production of short-chain fatty acids (SCFAs) to altered immune activation and β-cell damage. Microbiota transferred from individuals at risk for T1D has been shown to accelerate disease in animal models, supporting a possible causal relationship. Although experimental models support mechanistic links between microbiota alterations and autoimmune diabetes, current human evidence remains largely associative. Together, these findings suggest that microbial and immune networks interact in a feedback manner that can sustain immune tolerance or promote autoimmunity depending on environmental and host factors. Understanding T1D as a state of disrupted microbial and immune integration provides a basis for restoring gut–pancreas communication and preserving β-cell integrity. Full article

The pancreas is an organ with two functions: endocrine and exocrine. The proper functioning of the pancreas depends on many factors. One of these is trace elements—precise control of trace element homeostasis is important for both the endocrine and exocrine parts. This review provides a comprehensive summary of current knowledge regarding the role of trace elements: iron (Fe), copper (Cu), cobalt (Co), iodine (I), manganese (Mn), zinc (Zn), silver (Ag), cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se) in pancreatic physiology and their influence on the pathogenesis of key diseases of this organ, such as diabetes (DM), acute (AP) and chronic pancreatitis (CP), autoimmune pancreatitis (AIP), and pancreatic cancer (PC). Trace elements, including Fe, Cu, Zn, Se, and Mn, play a fundamental role in maintaining endocrine and exocrine homeostasis, participating in insulin synthesis, stabilizing digestive enzymes, and the functioning of antioxidant systems. It has been demonstrated that disturbances in their concentrations lead to the activation of pathological molecular pathways, including oxidative stress, chronic inflammation, and beta-cell apoptosis. In the context of diabetes, excess Fe promotes ferroptosis, whilst exposure to heavy metals such as Cd, Pb, and Hg induces insulin resistance and pancreatic islet dysfunction. In the course of pancreatitis, elements such as Zn and Se exhibit protective potential by stabilizing tissue barriers, whereas toxic metals impair ion transport, exacerbating fibrotic processes. Furthermore, analysis of available data indicates a significant association between heavy metal accumulation and pancreatic carcinogenesis, driven by DNA damage and oncogene modulation. Understanding pancreatic metallomics opens new prospects for early diagnosis, environmental prevention, and the development of targeted therapeutic strategies that restore the body’s micronutrient balance. Full article