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摘要： Type 1 diabetes is characterized by the destruction of pancreatic beta cells. Genetic factors account for ~50% of the total risk, with variants in the Human Leukocyte Antigen (HLA) region contributing to half of this genetic risk, with research historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS ) utilizing single nucleotide polymorphisms (SNPs) or HLA alleles from four ancestry groups (Admixed African (AFR; T1D GRS ), Admixed American (AMR; T1D GRS ), European (EUR; T1D GRS ), Finnish (FIN; T1D GRS ) and across ancestry (ALL; T1D GRS ). We assessed the performance of genetic risk scores in each population to determine transferability of constructed scores. A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRS models. Generated T1D GRS models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. Performance of each T1D GRS model was assessed using Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) and compared statistically. Each T1D GRS model included a different number of conditionally independent HLA region SNPs (AFR, n = 5; AMR, n = 3; EUR, n = 38; FIN, n = 6; ALL, n = 36) and HLA alleles (AFR, n = 6; AMR, n = 5; EUR, n = 40; FIN, n = 8; ALL, n = 41). The ROC AUC values of T1D GRS from SNPs or HLA alleles were similar and ranged from 0.73 (T1D GRS applied to FIN) to 0.88 (T1D GRS to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRS ) or HLA alleles (T1D GRS ) performed uniformly well across all ancestry groups, ranging from 0.82 to 0.88 for SNPs, and 0.80 to 0.87 for HLA alleles. T1D GRS models derived from SNPs performed equivalently to those derive

关键词： 右归丸   软骨细胞   丝裂原活化蛋白激酶/核因子-κB信号通路   凋亡   自噬  

摘要： 目的 研究右归丸通过丝裂原活化蛋白激酶p38-MAPK(p38-MAPK)/核因子-κB(NF-κB)信号通路调控肿瘤坏死因子-α(TNF-α)诱导软骨细胞自噬抑制凋亡的机制。方法 选择大鼠原代软骨细胞细胞分为空白组、模型组、右归丸含药血清组、对照组。采用CCK8检测软骨细胞增殖；TUNEL法检测软骨细胞凋亡情况；ELISA法检测各组软骨细胞上清液中IL-1β、IL-6水平；免疫荧光法测定软骨细胞Beclin1、微管相关蛋白轻链3B(LC3B)表达、凋亡相关蛋白B淋巴细胞瘤-2(Bcl-2)、Bcl-2相关X蛋白（Bax）表达水平；Western-blot法检测软骨细胞p-p38-MAPK,p-P65、Beclin1、LC3BⅡ/Ⅰ、Bcl-2、Bax、含半胱氨酸的天冬氨酸蛋白水解酶-3(Caspase-3)蛋白表达水平。结果 与模型组相比，右归丸组和对照组软骨细胞增殖抑制率均较低（P<0.05），软骨细胞凋亡率均较低（P<0.05），软骨细胞上清液中IL-1β、IL-6水平较低（P<0.05），软骨细胞Bax表达水平均较低，Bcl-2、Beclin1、LC3B表达水平较高（P<0.05），软骨细胞p-p38-MAPK、p-P65、Bax、Caspase-3表达水平均较低，LC3BⅡ/Ⅰ较高（P<0.05），右归丸组与对照组上述指标相比无差异（P>0.05）。结论 右归丸能够通过抑制p38-MAPK/NF-κB信号通路来调节软骨细胞自噬，抑制软骨细胞凋亡，减轻炎症反应，发挥软骨细胞保护作用。

关键词： hidradenitis suppurativa   scintigraphy   anti-TNF-alpha   diagnosis  

摘要： Shedding light on Hidradenitis Suppurativa activity: a pilot study to evaluate the potential of [99mTc]Tc-anti-TNF-alpha scintigraphy. Background/Objectives: Hidradenitis suppurativa (HS), also known as acne inversa and Verneuil's disease, is a chronic and non-contagious auto-inflammatory disease of pilo-sebaceous units that can lead to severe complications and sequelae. The actual prevalence of HS is unknown due to diagnostic delay and/or misdiagnosis, but it is estimated to affect 0.00033-4.1% of the general population worldwide. Only severe cases are referred for imaging assessment, and the final diagnosis is mostly established on a clinical basis. Here, we present a pilot study aiming to evaluate clinically active inflammatory disease in patients with HS using [99mTc]Tc-anti-TNF-alpha scintigraphy. Methods: Four patients (2 male, 2 female) had their HS clinical features measured through the HS-PGA and Hurley Score and compared to [99mTc]Tc-anti-TNF-alpha scintigraphy findings. Results: Scintigraphy with [99mTc]Tc-anti-TNF-alpha showed abnormal uptake in clinically active lesions of HS and also detected some clinically unknown potential active lesions, later confirmed by clinical reassessment after the imaging. Conclusions: Our results suggest that scintigraphy with [99mTc]Tc-anti-TNF-alpha may be able to detect increased radiotracer uptake in most clinically identified active lesions in this pilot cohort. While promising, due to the inherent limitations of this pilot study, more studies need to be carried out to arrive at a definitive diagnostic assessment of active inflammatory disease using this method.

关键词： HLA antigens   T-cell epitopes   non-specific lipid transfer proteins   Pru p 3 allergen   Ole e 7 allergen  

摘要： Concomitant sensitisation to non-specific lipid transfer proteins (nsLTPs) from olive pollen (Ole e 7) and peach (Pru p 3) has been observed in the south of Spain. In the search for reasons to explain this observation, we studied a potential causal relationship between Human Leukocyte Antigen (HLA) molecules and nsLTP sensitisation. For this purpose, eighteen Ole e 7-monosensitised (MONOLE) patients, 22 Pru p 3-monosensitised (MONPRU) patients, and 22 bisensitised (BI) patients were genotyped for HLA class II alleles. Complementarily, T-cell epitopes were predicted with the Immune Epitope Database analysis tool to test HLA epitope presentation. Our results showed a significant increase in DRB1*11 and DQB1*03 frequencies in MONPRU patients and DRB1*04 frequency in MONOLE patients. Additionally, T-cell epitope analysis revealed high binding affinity between the predicted Pru p 3 epitopes and DRB1*11 and between the predicted Ole e 7 epitopes and DRB1*04, suggesting that presentation of these epitopes may be favoured and predisposing individuals to sensitisation. Conversely, low DQB1*05 frequency and poor binding ability of predicted epitopes from both nsLTPs postulated this allele as a possible protective factor to sensitisation. Variations in the binding affinity between nsLTP epitopes and HLA molecules may underlie individual susceptibility to nsLTP allergy.

关键词： Children   Adolescents   Active tuberculosis   IFN-gamma   IL-2   Combined detection  

摘要： ObjectiveThis study aimed to conduct a combined detection of Mycobacteriumtuberculosis (MTB) infection using the tuberculosis (TB)-specific cytokine interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) release assays in hospitalized children and adolescents with TB, evaluate the clinical value of this technique in the diagnosis of active TB in children and adolescents, and to analyze the related influencing factors. MethodA retrospective study was conducted to collect data from suspected pediatric and adolescent TB patients hospitalized at Chengdu Public Health Clinical Medical Center between April 2022 and December 2024. The combined detection of MTB infection using IFN-gamma and IL-2 release assays (referred to as "dual-factor detection of TB infection") was carried out. Microbiological or molecular biological test results of MTB were also obtained. A total of 904 patients diagnosed with TB and 176 non-TB patients were included in the analysis of the effectiveness of dual-factor TB infection testing and related influencing factors. ResultsThe combined detection of IFN-gamma and/or IL-2 demonstrated improved diagnostic performance for active tuberculosis (ATB), with a sensitivity of 91.04% and specificity of 65.34% (AUC = 0.782, 95% CI 0.745-0.818). While IFN-gamma and IL-2 levels showed no significant differences between MTB-positive and MTB-negative subgroups within the TB cohort (IFN-gamma: 365.52 vs. 382.11 pg/ml;IL-2: 241.56 vs. 213.12 pg/ml), both cytokines were markedly elevated in the TB group compared to non-TB controls (IFN-gamma: 68.1 pg/ml;IL-2: 41.68 pg/ml). Age-related variations were observed in IFN-gamma (P < 0.05) but not IL-2 concentrations. Untreated patients exhibited higher median levels of IFN-gamma (397.9 vs. 306.0 pg/ml) and IL-2 (239.2 vs. 173.3 pg/ml) than treated individuals. Among 904 ATB cases, 8.96% (81/904) were false-negative for both cytokines. Multivariate analysis identified advanced age, retreatment TB, pleural effusion, and TST

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   Mycobacterium tuberculosis   immunosuppressive epitopes   IL-10   Tregs   autoimmunity  

摘要： Introduction italic>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 its probable immunoregulatory role. While it holds potential for treating autoimmune diseases, its impact on infection 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 possible role of Acr1 and its immunosuppressive epitope F18 as therapeutic agents for inducing suppressive Tregs, which may help in the management of autoimmune diseases.

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

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 Digitalis purpurea L., using tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma)-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-kappa B, 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   italic>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。