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关键词： pediatric   Crohn's disease   anti-TNF  

摘要： Background The 2021 ECCO-ESPGHAN guideline on the medical management of pediatric Crohn's disease promotes early risk stratification and top-down anti-TNF for patients deemed high risk of severe disease *** We aimed to objectively assess the risk-benefit profile of the guideline's risk stratification policy and guidance on top-down anti-TNF in a nationwide population-based cohort *** Using a prospectively identified nationwide cohort of all new pediatric patients (<17 years) diagnosed with Crohn's disease in Scotland between January 1, 2016 and December 31, 2020 and retrospectively applying the current management algorithm, we explored the guideline's ability to accurately risk stratify patients. Phenotypic and treatment data were retrospectively collected from electronic medical records with a maximum follow-up of 18 months *** Four hundred and eighteen children (258/418 [62%] male;median [interquartile range {IQR}] age at diagnosis: 13.2 [11.2-14.8] years) were included. High-risk phenotype was present in 224/418 (54%) with 53/224 (24%) of high-risk patients not requiring anti-TNF therapy within 18 months of diagnosis. Conversely, 78/194 (40%) of the low-risk group received anti-TNF within 18 months. High-risk patients were more likely to require anti-TNF (171/224 [76%] vs 78/194 [40%], P < .001) and had shorter median (IQR) time to anti-TNF start (5.0 [1.0-8.0] months vs 6.5 [3.3-13.0] months, P = .01).Conclusions Our data support the guideline's ability to identify patients more likely to require early treatment escalation. However, this approach would have led to potential over- and under-treatment in a substantial proportion of patients. This underscores the importance of frequent and comprehensive monitoring, along with flexible treatment strategies that adapt to changes in disease status. In a historic nationwide cohort of patients with pediatric Crohn's disease categorized as high or low risk using the 2021 ECCO-ESPGHAN

摘要： The human leukocyte antigen (HLA) region is highly diverse and plays a crucial role in immune regulation and antigen presentation. Accurate HLA typing is essential for understanding disease susceptibility, transplantation compatibility, and pharmacogenetics. However, its application in African descent populations is challenging due to complex linkage disequilibrium patterns and the lack of ancestry-matched populations in HLA reference panels. Here, we leveraged the latest whole-genome sequencing (WGS) data from UK Biobank African individuals to perform better HLA genotyping, and further utilized allelic and haplotypic data to explore population genetics patterns of this region. With WGS-inferred HLA alleles, we identified specific admixture patterns (predominant West and East African and minor European ancestries) within British African population, revealing their complex evolutionary history. Not only did we reveal the genetic diversity within this population, but also highlighted its differences from African Americans, ancestral Africans, and other global populations. We further identified regional ancestry differences in the HLA genomic region, highlighting discordance between global and local admixture estimates. British Africans also presented unique HLA frequency distributions for both typical and disease-associated alleles or haplotypes. These findings emphasize the need for expanding African-specific HLA reference panel and prove better HLA typing can be achieved by coupling sequencing technologies with computational approaches. The HLA genetic characteristics observed in British Africans provide valuable insights into population-specific immune responses and susceptibility. Overall, this study advances our understanding of HLA diversity and genetic admixture in British African population, with important implications for both disease mechanism and clinical utility.

关键词： Interleukin   IL-17D   Immune regulation   Chub mackerel  

摘要： Interleukin-17D (IL-17D) is a pro-inflammatory cytokine implicated in T helper 17 cell-mediated immune responses. Although its role in mammalian immunity is well established, its function in fish remains relatively unexplored. This study delves into the functional characteristics of IL-17D in chub mackerel (Scomber japonicus). We identified and characterized a chub mackerel IL-17D homolog (SjIL-17D) and investigated its spatial and temporal expression patterns, as well as the impact it has on downstream gene expression, apoptosis, cell proliferation, and nitric oxide (NO) production. SjIL-17D exhibited a wide tissue distribution, showing the highest expression in the blood, followed by the brain and skin. Upon immune challenges with polyinosinic:polycytidylic acid, lipopolysaccharide (LPS), Vibrio harveyi, and Streptococcus iniae, SjIL-17D expression was significantly upregulated in the blood. Functional analysis revealed that recombinant SjIL-17D (rSjIL-17D) stimulated the expression of pro-inflammatory cytokines, transcription factors, mitogen-activated protein kinases, and antiviral response genes in fish cell lines. Furthermore, rSjIL-17D attenuated LPS-induced apoptosis, promoted M1 macrophage polarization, and enhanced wound healing. Additionally, rSjIL-17D was found to stimulate NO production in macrophages and exhibit antiviral activity against viral hemorrhagic septicemia virus. These findings collectively demonstrate the crucial role that IL-17D plays in regulating immune responses in chub mackerel, providing valuable insights into the innate immune mechanisms of this economically important fish species.

关键词： Oral squamous cell carcinoma   Interleukin-1 receptor antagonist   Type I interferon response   Interferon alpha   Interferon beta  

摘要： Interleukin-1 receptor antagonist (IL1RA) is an anti-inflammatory and anti-tumor protein, and a member of the Interleukin-1 (IL-1) family. Our previous finding showed that IL1RA is a tumor marker for oral squamous cell carcinoma (OSCC), but the exact mechanism is unknown. The present study aims to investigate the biological role of IL1RA in the progression of OSCC in vitro and in vivo and the underlying molecular mechanism. IL1RA was lowly expressed in OSCC specimens and cells, and its overexpression significantly inhibited the proliferation and migration of OSCC cell lines CAL27 and HN6. In nude mice bearing OSCC xenografts, in vivo overexpression of IL1RA significantly reduced tumor growth without influencing epithelial-mesenchymal transition (EMT). Differentially expressed genes (DEGs) in OSCC cells overexpressing IL1RA were identified by RNA sequencing (RNA-seq), and they were significantly enriched in cancer-associated signaling pathways like type I interferon response. IL1RA upregulated interferon alpha (IFNA) and interferon beta (IFNB), known for their anti-cancer properties, in OSCC cells and specimens. In conclusion, IL1RA inhibits the malignant progression of OSCC by mediating the type I interferon response.

关键词： RAG deficiency   anti-IFN-a autoantibodies   viral infection  

摘要： Background: Autoantibodies against IFN-alpha (anti-IFN-alpha) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined. Objective: We described the clinical and immunologic findings linked to anti-IFN-alpha IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation. Methods: We measured anti-IFN-alpha IgG by enzyme-linked immunosorbent assay in 80 RAG-deficient patients with curated clinical and immunologic data from a multinational collaboration. Results: Forty-eight patients (60.0%) had positive anti-IFN-alpha at baseline;these patients were typically older at time of testing, fulfilled the phenotype of delayed-onset combined immunodeficiency with granuloma and/or autoimmunity (70.8% vs 31.3%, P = .001), and had a history of more frequent viral infections, mainly from the Herpesviridae family (62.5% vs 21.9%, P < .001). These patients also showed higher levels of serum immunoglobulins and expanded populations of peripheral blood autoreactive-prone (CD19(hi)CD21(lo)) (14.3 vs 5.2%, P = .016) and double-negative (IgD(-)CD27(-)) B cells (12.8 vs 5.8%, P = .001). In cases with longitudinal evaluation, anti-IFN-alpha titers were largely stable, although an increase was observed with concurrent active cytomegalovirus infections. Despite some decline after transplantation, these autoantibodies persisted during follow-up. Conclusions: Anti-IFN-alpha autoantibodies reflect immune dysregulation in partial RAG deficiency. Their production is likely aggravated by environmental factors, especially frequent viral infections. Further studies are needed to define their pathogenic role in RAG deficiency.

关键词： IL-23 receptor   leukopenia   Mulberroside C   neutrophil   RASGRP1  

摘要： Chemotherapy- and radiotherapy-induced leukopenia is a common challenge in cancer treatment, with a significant dearth of effective therapeutic options. IL-23 receptor (IL-23R) signaling holds the potential for promoting neutrophil generation and maturation, yet the underlying mechanisms remain elusive. This study investigates the molecular mechanism and efficacy of Mulberroside C (MC) in alleviating leukopenia via IL-23R signaling. In vitro, flow cytometry, nitroblue tetrazolium reduction assay, and Giemsa staining were employed to evaluate MC's impact on neutrophil differentiation in NB4 and HL-60 cell lines. The antibacterial activity of MC was assessed using an agar plate assay. In vivo, leukopenia models induced by irradiation and cyclophosphamide were established in zebrafish and mice to determine MC's effect on neutrophil recovery. Mechanistic studies involved RNA sequencing, network pharmacology analysis, molecular docking, quantitative real-time PCR (qRT-PCR), and Western blotting to explore the associated signaling pathways. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to identify MC's targets. MC significantly enhanced neutrophil maturation in a dose-dependent manner, facilitating leukopenia recovery. Mechanistically, MC binds to IL-23R, upregulating G-CSF, GM-CSF, and RASGRP1 and activating the RAS/ERK signaling pathway. Notably, the upregulation of RASGRP1 by MC supports the generation of fully functional neutrophils, compared to those induced by G-CSF and GM-CSF alone. This study provides the first evidence that MC promotes neutrophil generation and antimicrobial activity through the IL-23R-mediated pathway, offering a promising therapeutic strategy for leukopenia.