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关键词： Beh & ccedil   et's uveitis   CD44   IL-17A   neutrophil extracellular traps   positive feedback loops  

摘要： Beh & ccedil;et's uveitis (BU) is a severe ocular manifestation of Beh & ccedil;et's disease, typically accompanied by abnormal neutrophil infiltration and hyperactivation. However, the underlying causes of excessive neutrophil extracellular traps (NETs) production and mechanisms by which NETs contribute to the pathogenesis of BU remain incompletely understood. Neutrophils from BU patients exhibit a higher propensity for NETs release compared to healthy controls. In the experimental autoimmune uveitis (EAU), neutrophils are observed to exert pro-inflammatory effects through NETs. Clearing NETs can inhibit T helper 17 (Th17) cell differentiation and significantly alleviate EAU symptoms. In vivo and in vitro experiments demonstrate neutralizing IL-17A markedly reducing neutrophil infiltration and NETs formation in EAU. Single-cell RNA sequencing confirms that CD44 plays a key role in mediating interactions between NETs and Th17 cells. Antagonizing CD44 inhibits the proportion of Th17 cells and NETs formation. Multiplex immunofluorescence and cell communication analyses further demonstrate interactions and colocalization between NETs and CD44(high)CD4(+)T cells in EAU. NETs induce Th17 differentiation via upregulating CD44, and in turn, Th17 cells secrete IL-17A to recruit neutrophils and promote NETs formation. Interrupting NETs-CD44-IL-17A feedback loop may be a potential therapeutic target for BU.

关键词： atopic dermatitis   CRTH2   eosinophils   HLA-DR   Siglec-8  

摘要： Atopic dermatitis and other type 2 immune response diseases are often linked to elevated eosinophil levels in the blood. Although the role of eosinophils in atopic dermatitis pathophysiology is suspected, it remains unclear. The development of new treatments targeting the type 2 response, particularly cytokines involved in eosinophil activation and chemotaxis, makes it necessary to identify potential eosinophil profiles in atopic dermatitis that may respond to these treatments. A prospective study was conducted comparing blood eosinophil phenotypes in patients with moderate to severe atopic dermatitis (n = 19) without recent systemic treatment to healthy individuals (n = 19). The primary outcome was the membranous phenotypic signature of eosinophils, assessed by flow cytometry. Most patients with atopic dermatitis (84%) had early onset in childhood, a severe disease (mean SCORing Atopic Dermatitis of 57.5), and elevated blood eosinophil counts (310 per mu L in atopic dermatitis vs 120 in healthy individuals, P < 0.0001). Patients with atopic dermatitis exhibited lower CRTH2 on eosinophils but higher levels of human leukocyte antigen-DR isotype and Siglec-8 compared to healthy individuals. Other surface proteins showed no significant differences. Clustering analysis confirmed increased Siglec-8 in patients with atopic dermatitis. Additionally, patients with atopic dermatitis had higher serum levels of type 2 immune response markers such as eotaxin-2, IL-5, IL-3, and TARC. Circulating eosinophils in patients with atopic dermatitis show a distinct phenotypic profile, suggesting a role in atopic dermatitis pathophysiology and potential involvement in differential treatment responses. [GRAPHICS] .

关键词： HLA-C   NGS   novel allele  

摘要： Novel HLA-C*07:1165, HLA-C*07:1166, HLA-C*07:02:161 alleles and confirmatory HLA-C*07:02:156 allele were detected during the HLA typing process.

关键词： Consent   Immuno-modulation   Immunological   Ligand   Messenger ribonucleic acid (mRNA)   Molecular genetic   Pathogenesis   Polymorphism   Prevalence  

摘要： BackgroundNon-alcoholic fatty liver disease (NAFLD) in non-obese patients is pathophysiologically distinct, exhibiting common immunological link with type-2 diabetes mellitus (T2DM). This study aims to delineate the role of Toll-like receptor 2 (TLR2)-mediated immuno-modulation along with its association with fibroblast growth factor receptor 4 (FGFR4) and its ligand fibroblast growth factor 19 (FGF19) in the pathogenesis of NAFLD without or with *** samples were collected from patients with NAFLD (n = 90), NAFLD with T2DM (n = 90) and healthy cohorts (n = 90) with consent and clinical records. Real-time polymerase chain reaction (PCR), enzyme-linked immunoassay (ELIZA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to analyze messenger ribonucleic acid (mRNA), protein expression and gene *** molecular genetic analysis revealed the prevalence of variant allele(A) in FGFR4 gene in both cases compared to controls. The mRNA expression of FGF19 and TLR2 exhibited significant upregulation in NAFLD without T2DM compared to NAFLD with T2DM. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) showed upregulation in both disease cohorts compared to control while IL-10 showed significant downregulation in NAFLD with T2DM compared to the other two cohorts. Correlation analysis between FGF19 and TLR2 revealed significant positive association in both NAFLD with and without T2DM. The Th1:Th2 ratio showed significant upregulation in NAFLD with T2DM compared to NAFLD without *** conclusion, elevated serum endotoxin levels appear to contribute to NAFLD and T2DM development. Upregulated FGF19 seems to be protective against developing T2DM in NAFLD patients. Higher TLR2, TNF-alpha and IL-12 expression in NAFLD without T2DM suggests a Th1 bias in its pathogenesis, while reduced IL-10 in NAFLD with T2DM implies a more skewed Th1 state in this condition.

关键词： cost-effective   high-throughput   HLA   long-read sequencing   nanopore   native barcoding  

摘要： HLA typing of large donor registries and biobanks as well as acute single patient/donor samples remains expensive, slow and logistically challenging, despite recent developments in the field. We have tested and validated a cost-effective, accurate and highly scalable method for typing specific genes in the HLA region. This enables HLA typing from 1 to 96 individuals simultaneously, using a targeted PCR and Native Barcoding kit from Oxford Nanopore Technologies. A primer set for seven HLA genes (HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1) was developed to work in a multiplex PCR reaction. The resulting amplicons provide a possible four-field resolution of the HLA Class I genes and G-group resolution of the HLA Class II genes. The entire process, from DNA to HLA typing result, takes a total of 5.5-10.5 h depending on the number of samples processed simultaneously. Data analysis was conducted using NGSEngine-Turbo from GenDx (Utrecht, The Netherlands), with analysis time ranging from 1 to 5 min per sample. Samples from 96 Danish registered stem cell donors were typed using this method. One allele out of 1128 analysed alleles was inaccurately called homozygous, leading to an accuracy of 99.91%. The rapid turnaround, low cost and high accuracy make this new method highly relevant for HLA typing of large biobanks and donor registries, as well as for acute single samples. HLA typing can be obtained within 1 day, with a cost per sample of approximately 7 when 96 samples are sequenced simultaneously.

关键词： innate lymphoid cells   pancreatic ductal adenocarcinoma   tertiary lymphoid structures   interleukin-33  

摘要： Tertiary lymphoid structures (TLS) are associated with anticancer immunity, but the mechanisms underpinning their formation remain poorly understood. Amisaki et al. have recently shown that IL-33 mediates ILC2 gut-tumoral migration and promotes TLS formation in pancreatic ductal adenocarcinoma (PDAC) by inducing group 2 innate lymphoid cell (ILC2) Ltb expression. This study highlights new potential therapeutic avenues to enhance immunotherapy.