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关键词： ADA2 deficiency   Beh & ccedil   et's disease   Rheumatic disease   Children   HLA-B*51   Autoinflammatory  

摘要： Purpose Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease resulting from biallelic loss-of-function mutations in ADA2 gene. It has variable clinical manifestations, some of which can mimic Beh & ccedil;et's disease (BD). Herein, we present a family of three siblings diagnosed with DADA2, two of whom were initially misdiagnosed as BD based on clinical phenotype including positive human leukocyte antigen B51 (HLA-B*51). Methods Gene mutational analysis was performed by whole exome (WES) and Sanger sequencing. Results We reported two siblings presented with recurrent oral ulcers, fever, arthritis, and skin lesions, alongside elevated inflammatory markers and HLA-B*51 positivity, leading to an initial misdiagnosis of BD. Genetic testing later revealed a homozygous ADA2 variant (c.139G > A ***47Arg) in both siblings and their asymptomatic younger sister, confirming DADA2 diagnosis. Thereafter, we reviewed the literature to identify other patients misdiagnosed with BD but later found to have DADA2. This resulted in a cohort of 10 DADA2 patients, including our two reported siblings. The median time from symptoms onset to the final diagnosis of DADA2 was 7 years. All patients exhibited BD-like phenotype, except for uveitis, and 8 were HLA-B*51 positive, which likely contributed to the diagnostic confusion. Conclusion These findings highlight the broad clinical spectrum of DADA2, which can resemble BD, and suggest that HLA-B*51 positivity in DADA2 may further complicate diagnosis. Clinicians should maintain a high index of suspicion for DADA2 in early-onset BD-like cases, particularly without uveitis, or a family history of similar symptoms. Further studies are warranted to explore HLA-B*51 role in DADA2 phenotype.

关键词： Maniq people   Hunter-gatherer   HLA diversity   Positive selection   Balancing selection  

摘要： The Maniq, a small and isolated nomadic hunter-gatherer population from the rainforests of Southern Thailand, offer a unique context for investigating how demographic history, genetic drift, and pathogen-driven selection shape human leucocyte antigen (HLA) diversity. Using high-coverage whole-genome data from 21 individuals (12 unrelated), we genotyped HLA alleles with HLA-HD and T1K, identifying 32 alleles in classical and 14 in non-classical HLA genes. Although overall HLA diversity was comparatively low, a few alleles at each locus occurred at high frequency, mirroring patterns observed in other small, isolated populations. Principal-component analysis clustered the Maniq with other Austroasiatic-speaking Semang hunter-gatherers (Jehai, Kintaq) on the Malay Peninsula and, intriguingly, with the Austronesian-speaking Tao of Taiwan, indicating shared immunogenetic features across linguistic boundaries. Despite reduced diversity, multiple loci bore signatures of both long-term balancing and recent positive selection. Several SNPs under selection were in complete linkage disequilibrium with eQTLs known to influence responses to hepatitis B virus (HBV) and other pathogens, suggesting that pathogen-driven pressure-in particular HBV-may have contributed to recent HLA evolution in the Maniq. These findings provide critical insights into how demographic constraints and pathogen landscapes converge to shape HLA diversity and evolution. In light of increasing infectious disease burdens in indigenous communities, our results underscore the importance of studying small, isolated populations to better understand the adaptive significance of HLA genes.

关键词： Diabetic kidney disease   Neutrophil extracellular traps   Inflammation   Subtype   IL-33  

摘要： BackgroundChronic inflammation is well recognized as a key factor related to renal function deterioration in patients with diabetic kidney disease (DKD). Neutrophil extracellular traps (NETs) play an important role in amplifying inflammation. With respect to NET-related genes, the aim of this study was to explore the mechanism of DKD progression and therefore identify potential intervention *** NET-related DEGs were screened via differential expression analysis and three machine learning methods, namely, LASSO, SVM-RFE and random forest. Consensus clustering was performed to analyze NET-related subtypes in DKD patients. KEGG enrichment analysis, GSEA, GSVA, ssGSEA and ESTIMATE were conducted to explore the molecular features of DKD patient subtypes. Leveraging single-nucleus RNA-seq datasets, the "scissor" and "bisqueRNA" algorithms were applied to identify the composition of renal cell types in DKD patient subtypes. Soft clustering analysis was performed to obtain gene groups with similar expression patterns during the development and progression of DKD. The correlations between hub NET-related DEGs and clinical parameters were mined from the Nephroseq V5 database. The core gene among the hub NET-related DEGs was selected by calculating semantic similarity. "Cellchat" algorithm, immunostaining, ELISA and flow cytometry were performed to explore the expression and function of the core gene. The Drug-Gene Interaction Database (DGIdb) was searched to identify candidate *** hub NET-related DEGs, namely, ACTN1, ITGB2, IL33, HRG, NFIL3 and CLEC4E, were identified. On the basis of these 6 genes, DKD patients were classified into 2 clusters. Cluster 1 patients, with higher NET scores, were evidently more immune-activating than those of cluster 2. Markedly increased numbers of immune cells, fibroblasts and proinflammatory proximal tubular cells were observed in cluster 1 but not in cluster 2. Cluster 1 also represented a more clinically advanced

关键词： Asthma   Airway inflammation   Decline   Eosinophils   Lung Diseases  

摘要： Background Asthma is associated with accelerated rate of FEV1 decline. ObjectiveTo determine predictive factors associated with accelerated FEV1 decline in adult asthma and evaluate sputum cytokines as potential biomarkers for airflow decline. Methods We recruited 125 asthmatics evaluated at the asthma clinic of Li & egrave;ge and reevaluated them at least 5 years later. Clinical, functional and inflammatory characteristics were compared between patients with accelerated decline (FEV1 decline > 0.85% pred.y(-1)) and others. Predictive factors were highlighted with linear regression analysis. Sputum EGF, VEGF, FGF, IL5, IL8, TGF-beta, and IgE levels were measured in 58 of these patients at both visits by Human XL cytokine Luminex Performance assay and Elisa. Results Post-BD FEV1 decline was 0.06 +/- 2.44% pred.y-1 in the overall population. Median (IQR) time between visits was 66 (62 - 86) months. The multivariable analysis showed that an increase in blood eosinophils over time (Delta BEC) (Reg. Coef. (95%CI): 0.002 (0.001 to 0.004), p = 0.005)) and onset of asthma (0.04 (0.003 to 0.07), p = 0.036) were independently associated with FEV1 decline. IL8 levels measured at baseline were higher (499 (408-603) pg/ml, p = 0.0040) in patients with accelerated decline compared to others (143 (88-308) pg/ml). Conclusion In this study, we have confirmed that an increase in blood eosinophil counts over a follow-up of at least 5 years and later onset of asthma are associated with accelerated annual FEV1 decline. Moreover, high sputum IL8 levels could be a risk factor for accelerated decline in asthma patients.

关键词： Cancer immunotherapy   Epitope prediction   HLA   Machine learning   MHC  

摘要： Cancer immunotherapy hinges on accurate epitope prediction for advancing vaccine development. VaxOptiML (available at https://***/) is an integrated pipeline designed to enhance epitope prediction and prioritization. This study aims to develop and deploy a robust tool for accurate prediction and prioritization of highly immunogenic and optimized MHC-I and MHC-II T-cell epitopes for cancer vaccine development and immunotherapy. Utilizing a curated dataset of experimentally validated epitopes and employing sophisticated machine learning techniques, VaxOptiML features three models: epitope prediction from target sequences, personalized HLA typing, and prioritization the predicted epitopes based on immunogenicity scores. Our rigorous data extraction, cleaning, and feature extraction processes, coupled with model building, yield exceptional accuracy, sensitivity, specificity, and F1 score, surpassing existing prediction methods. Comprehensive visual representations underscore VaxOptiML's robustness and efficacy in accelerating epitope discovery and vaccine design for cancer immunotherapy. Deployed via Streamlit for public use, VaxOptiML enhances accessibility and usability for researchers and clinicians, demonstrating significant potential in cancer immunotherapy.

关键词： IL-2R beta   Inborn errors of immunity   Immunodeficiency   Autoimmunity   Hematopoietic stem cell transplantation   Conditioning  

关键词： IL-21   Inflammation   Lymphocytes   S. aureus   Septic arthritis   TGF-beta   Th17/Treg  

摘要： Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, na & iuml;ve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-beta in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-beta and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-beta 1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-kappa B, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-beta and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-beta and IL-21 could pr

关键词： Type 1 diabetes   Islet antigen-specific T cells   T cell epitopes   Islet-specific autoantibodies  

摘要： A proportion of patients with new-onset diabetes share similar symptoms with type 1 diabetes (T1D) patients but they are negative for islet antigen-specific autoantibodies. This study was to develop an islet antigen-specific CD8(+) T-cell assay to provide autoimmune evidence regarding these "suspected" T1D patients. HLA-A*0201 individuals with autoAbs(+) T1D, autoAbs(-) suspected T1D, and type 2 diabetes, along with HLA-A*0201 healthy controls were recruited. Using interferon-gamma enzyme-linked immunospot assays, the percentages of participants in each group with various islet antigen-specific CD8(+) T cells were determined. Sixteen out of the 28 islet antigen-specific epitopes tested were T1D specific, meaning that there was a significantly (P < 0.05) greater epitope positivity rate in the autoAbs(+) T1D cohort than in the healthy controls. Using a cutoff value of two positive epitopes, the 16-epitope panel led to a sensitivity of 75.0% and a specificity of 94.4% regarding the autoAbs(+) T1D patients. Even when using an optimized five-epitope panel, the results were highly accurate. Notably, in the application phase of the study, 77.8% of a new cohort of autoAbs(-) suspected T1D patients exhibited positivity when using the five-epitope optimized panel. This highly accurate method, especially for pediatric patients, will improve clinical diagnosis and etiological classification of autoimmune T1D.

关键词： ADAMTS-8   Colorectal cancer   Transcriptional regulation   Inflammation   IL-6  

摘要： BackgroundADAMTSs are extracellular matrix metalloproteinases that mainly process extracellular matrix components and closely related tumorigenesis. ADAMTS-8 is an anti-angiogenic member of the family and is dysregulated in common cancers. The tumor suppressor function of the ADAMTS-8 has been demonstrated in colorectal cancer. Although ADAMTS-8 plays a critical role in tumor progression, transcriptional regulatory features haven't been studied *** and methodsThe human ADAMTS-8 promoter was cloned into the pMetLuc Reporter vector. Basal promoter activity and the effect of the IL-6 on ADAMTS-8 promoter activity were determined by transient transfection assays in SW480 cells. QRT-PCR and Western blot analyses assessed the impact of IL-6 on ADAMTS-8 mRNA and protein expressions. Functional binding of the specific transcription factors to the ADAMTS-8 promoter region was evaluated by ChIP qPCR and *** results demonstrated that the ADAMTS-8 promoter includes multiple binding sites for transcription factors that could be activated in the inflammatory pathways. IL-6 stimulation increased ADAMTS-8 promoter activity, also mRNA, and protein expressions. Pathway inhibition studies showed that IL-6-mediated induction of ADAMTS-8 was achieved through p38/MAPK, NF-kappa B, PI3K, and SAPK/JNK pathways. STATs, Elk-1, and c-Jun functionally bind to the ADAMTS-8 promoter *** can be concluded that inflammation is a strong positive regulator of the ADAMTS-8 gene.

关键词： Tissue regeneration  

摘要： Inflammatory cells are crucial regulators of infection and regeneration that actively migrate to affected tissues. NF-kB and TNF-alpha (TNFα) are master regulators of immune signalling, but their importance for immune cell migration is much less well understood. We have therefore investigated how NF-kB and TNFα regulate both macrophage function and behaviour in vivo using a zebrafish model of tissue repair. We show that NF-kB activity differentially regulates TNFα activity through Tnf receptors 1a and 1b to control macrophage responses to injury. Loss of NF-kB in macrophages results in elevated TNFα expression and results in more directional migration. Impaired NF-kB activity in macrophages perturbs tissue regeneration, causes increased proliferation, altered pro- and anti-inflammatory gene expression and delays fin regeneration. We identify a crucial role for NF-kB modulation of TNFα signaling to regulate macrophage responses to tissue injury, which are necessary for effective fin regeneration. © The Author(s) 2025.