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关键词： Crohn's disease   HLA antigen and pancreatitis   Immunomodulators   Pancreatitis   Thiopurine side effects   Ulcerative colitis  

摘要： BackgroundAzathioprine (AZA)-induced pancreatitis is a significant adverse event affecting patients with inflammatory bowel disease (IBD). A genetic association with HLA-DRB1*07 and HLA-DQA1*02 alleles polymorphisms has been reported, but its prevalence and impact on Asian patients with IBD remain *** retrospective review of a prospectively maintained database of patients with IBD was done from January 2005 till December 2024. Patients who developed pancreatitis were tested for HLA association with HLA class II-DRB1*07 and HLA-DQA1*02 alleles. Duration of AZA, dose of AZA and other risk factors such as smoking, alcohol intake, steroid administration, previous history of pancreatitis and any other risk factors for pancreatitis were noted. These patients were compared with a matched control group of non-IBD patients undergoing human leukocyte antigen (HLA) typing for other *** 1751 patients with IBD, 441 (25.1%) were exposed to AZA 12/441 (2.7%) developed azathioprine-induced pancreatitis. Patients with pancreatitis had a significantly higher prevalence of the HLA-DRB1*07 and HLA-DQA1*02 haplotype compared to controls (8/12;66.6% vs. 1877/7361;25.4% p = 0.001089). The onset of pancreatitis occurred within a median of 15 days of initiation of AZA, with all cases being mild in severity. Rechallenge confirmed causality in one ***-induced pancreatitis occurred in 2.7% patients. The class-II HLA-DRB1*07 and HLA-DQA1*02 is an important marker for AZA-induced pancreatitis risk. Rechallenge should be avoided in patients with this HLA antigen. More data is required for pre-emptive HLA testing prior to initiation of azathioprine.

关键词： Acr1   IL-10   Mycobacterium tuberculosis   Tregs   autoimmunity   immunosuppressive epitopes  

摘要： INTRODUCTION:Mycobacterium tuberculosis (Mtb) is a Gram-positive bacterium that causes tuberculosis (TB). It remains viable for extended periods within host macrophages by entering a dormant state. Alpha crystallin 1 (Acr1) is a 16 kDa protein of Mtb and is reported to be highly upregulated in latent TB. Acr1 suppresses the host's immune system by impairing the differentiation and maturation of dendritic cells and macrophages. We hypothesize that Mtb judiciously utilizes its Acr1 protein to paralyse the immune system of the host by inducing the release of IL-10 and generating an immunosuppressive environment. METHODS:We employed in silico tools to identify highly promiscuous, IL-10-inducing and IL-6- non-inducing epitopes of Mtb. Moreover, the selected epitope was synthesized and tested for its suppressive activity and generation of Tregs. RESULTS:We identified the presence of a specific epitope in Acr1 (F18) that is responsible for bolstering the release of IL-10 and Tregs through in silico tools and verified the activity by in vitro assays. In hPBMCs, the F18 epitope could suppress the proliferation of CD4 T cells stimulated with PHA and expand the pool of Tregs in a dose-dependent manner. DISCUSSION:The F18 epitope from Mtb's Acr1 protein promotes IL-10 and Treg responses without triggering pro-inflammatory IL-6, suggesting a potential immunoregulatory role. While it holds potential for treating autoimmune diseases, its impact on infection tolerance in tuberculosis should be further investigated. CONCLUSION:Our findings suggest that the F18 epitope induces IL-10 production and Treg differentiation while inhibiting CD4+ T cell proliferation and IL-6 secretion, thereby promoting an immunosuppressive environment. Furthermore, this study highlights the potential of Acr1 and its immunosuppressive epitope F18 as therapeutic agents for inducing suppressive Tregs in the management of autoimmune diseases.

关键词： 3D human skin model   Digitalis purpurea   JAK/STAT   NF-κB   atopic dermatitis   desrhamnosyl acteoside   keratinocyte  

摘要： Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder affecting 10-20% of the population. In this study, we investigate the anti-inflammatory effect on the skin of eight compounds isolated from L., using tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-stimulated human keratinocytes (HaCaT cells) and a three-dimensional (3D) reconstructed human skin model. Among the tested compounds, desrhamnosyl acteoside exhibited the most potent activity, significantly reducing the secretion of pro-inflammatory cytokines (IL-6, IL-8) and chemokines (CCL17, CCL22), suppressing the expression of inflammatory proteins, and modulating key signaling pathways, including NF-κB, JAK2/STAT1, and MAPK. Notably, this is the first report demonstrating that desrhamnosyl acteoside simultaneously targets all three pathways, indicating a multi-modal mechanism distinct from conventional single-target approaches. In the 3D skin model, desrhamnosyl acteoside further exhibited barrier-protective effects by downregulating inflammatory mediators and upregulating epidermal differentiation markers such as involucrin and loricrin. These findings reveal a previously uncharacterized phytochemical with dual anti-inflammatory and barrier-restorative activities, supporting its potential as a novel therapeutic candidate for AD and other inflammatory skin diseases.

关键词： full genomic sequence   HLA   HLA-DQB1*06:97   PacBio sequencing  

摘要： We report the full genomic sequence of the HLA-DQB1*06:97 allele.

关键词： 猪囊尾蚴   丝氨酸蛋白酶抑制剂   优势抗原表位   鉴定表达  

摘要： 针对猪囊尾蚴丝氨酸蛋白酶抑制剂B6 (Ts-serpin B6)和4848 (Ts-serpin 4848)抗原表位暴露不充分，缺乏高特异性问题，拟通过筛选关键抗原表位增强抗原特异性。首先对Ts-serpin B6和Ts-serpin 4848基因序列进行生物信息学表位分析，筛选出优势抗原表位，设计特异性引物后经RT-PCR分别扩增靶基因片段。将纯化的PCR产物连接到pET28a(+)载体后转化至大肠杆菌DH5α感受态细胞，构建pET28a(+)-Ts-serpin B6、pET28a(+)-Ts-serpin 4848的分段原核表达载体，转入大肠杆菌BL21（DE3）中诱导表达，目的蛋白纯化后进行SDS-PAGE鉴定和Western-blot分析。SDS-PAGE结果显示，成功表达纯化了6个重组目的蛋白Ts-serpin B6(a)、Ts-serpin B6(b)、Ts-serpin B6(c)和Ts-serpin 4848(a)、Ts-serpin 4848(b)、Ts-serpin 4848(c)，其在大肠杆菌中主要以包涵体形式存在。Western-blot和ELISA结果表明重组蛋白Ts-serpin B6(a)和Ts-serpin 4848(a)与其他分段重组蛋白相比具有更强的反应原性和特异性。结论：明确Ts-serpin B6(a)和Ts-serpin 4848(a)是抗原的优势表位，为猪囊尾蚴病特异性诊断试剂研发提供了依据。

关键词： HLA   HLA-B   new alleles   next-generation sequencing  

摘要： Characterisation of the HLA-B*07:02:01:131, -B*35:08:01:14, -B*44:02:01:88 and -B*44:03:01:76 alleles in Spanish individuals.

摘要： Atopic dermatitis (AD) is a chronic dermatosis characterized by type-2 inflammatory responses, skin barrier anomalies and microbiome dysregulation. The variety of AD presentations necessitates a better understanding of the underlying disease mechanisms and the modulation of immune markers over a treatment course. Globally, the most used systemic therapies for moderate-to-severe AD are methotrexate (MTX) and ciclosporin (CyA). The TReatment of severe Atopic Eczema in children Trial (TREAT) was a randomized controlled trial (RCT) assessing the efficacy and safety of MTX and CyA. Peripheral blood samples from 18 TREAT participants were analysed in a longitudinal immunological study with a focus on cytokine-expressing CD4+ T cells. The analysis showed that both MTX and CyA were associated with a decreased percentage of interleukin (IL)-4 and IL-13 expressing CD4+ memory T cells, corresponding to improved disease severity. Patients receiving MTX experienced a more sustained decrease in IL-4 expressing T cells, which corresponds to the longer-term improved disease control observed in the MTX arm. Ciclosporin (CyA) and methotrexate (MTX) are both frequently prescribed drugs for the treatment of atopic dermatitis (AD) in children and young people. CyA has historically been the most commonly used conventional systemic treatment for severe paediatric AD, but MTX is being increasingly used as an alternative first-line conventional systemic treatment, especially in middle- and low-income settings. We found that MTX provides an effective and low-cost first-line systemic treatment for severe AD and is a suitable alternative to CyA. Both CyA and MTX are associated with a decrease in the percentage of interleukin (IL)-4 and IL-13 expressing CD4+ memory T cells, corresponding to an improvement in disease severity.

关键词： Nanoparticles  

摘要： Daily subcutaneous injections of recombinant interleukin-10 (IL-10) demonstrated encouraging but preliminary efficacy in certain tumour types during early phase clinical trials. However, these antitumour effects were not consistently replicated in larger trials, probably due to insufficient intratumoural recombinant IL-10 accumulation, which ultimately restricted clinical benefit. Here we show that intravenous injections of IL-10 messenger RNA (mRNA) nanoparticles (IL-10-mRNA@NPs) induce potent immune surveillance across diverse preclinical tumour models and mitigate systemic toxicities. In particular, IL-10-mRNA@NPs sustain in situ IL-10 production within tumours, promoting substantial infiltration and proliferation of cytotoxic T cells, activation and maturation of dendritic cells, and an augmented expression of major histocompatibility complex class I molecules in immunosuppressive orthotopic early stage hepatocellular carcinoma tumours. Moreover, in mice with orthotopic middle-to-late-stage hepatocellular carcinoma tumours, combining IL-10-mRNA@NPs with immune checkpoint blockades results in 43% of mice showing complete tumour eradication and a sixfold increase in median survival compared with mice treated with immune checkpoint blockades alone. Furthermore, this combination induces long-lasting antitumour immune memory, conferring 100% protection against tumour rechallenges. The intravenous IL-10-mRNA@NPs strategy may have potential to overcome the challenges associated with recombinant IL-10 in clinical trials across a broad spectrum of immunosuppressive tumours.