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关键词： Crohn’s disease   HLA genotypes   HLA-DQA1*05   anti-TNF therapy   anti-drug antibodies   immunogenicity   inflammatory bowel disease   pharmacogenetics   precision medicine   ulcerative colitis  

摘要： The emergence of anti-TNF agents has revolutionized the management of inflammatory bowel disease, yet a significant proportion of patients experience primary non-response or secondary loss of response due to immunogenicity. As the field of precision medicine advances, genetic predictors such as human leukocyte antigen (HLA) variants are gaining increasing attention. This review provides a comprehensive synthesis of current evidence on the role of HLA genotypes in inflammatory bowel disease susceptibility and disease behavior, with a focus on their mechanistic and clinical relevance in anti-TNF therapy. Special emphasis is placed on HLA-DQA1*05, a validated predictor of anti-drug antibody formation and reduced therapeutic durability. We explore the immunological basis of HLA-mediated immunogenicity, summarize pharmacogenetic and biomarker findings, and discuss how HLA typing may be integrated into treatment algorithms to improve patient stratification and long-term outcomes. As immunogenetics continues to inform clinical decision-making, understanding the interplay between HLA polymorphisms and therapeutic response offers new opportunities for biomarker-guided, personalized care in inflammatory bowel disease.

关键词： CD8   T细胞   HLA-A*02   HLA-E   共同提呈   表位   感染性疾病   综述  

摘要： 人类白细胞抗原（HLA）在免疫应答中发挥着关键作用。其中，HLA-A*02作为经典HLA-Ia类分子，通过提呈内源性抗原表位激活CD8+T细胞，从而在抗病毒免疫应答中发挥重要作用；而非经典HLA-Ib类分子HLA-E可通过与自然杀伤（NK）细胞表面CD94/NKG2结合，参与免疫稳态的调控。近年来研究发现，HLA-E同样能够提呈病原体及肿瘤等来源的抗原表位激活CD8+T细胞，并且其提呈的肽段序列与HLA-A*02提呈肽段高度相似，提示HLA-A*02与HLA-E可能通过协同或竞争机制，共同参与CD8+T细胞抗感染免疫应答。本文系统综述了HLA-A*02与HLA-E的结构特征及抗原提呈机制的异同，及其在感染性疾病中共同提呈病原体抗原表位的现象，深入探讨二者共同提呈抗原表位在宿主防御与免疫稳态维持中的可能作用。基于HLA-A*02与HLA-E共同提呈抗原表位来设计新型多肽疫苗，有望克服人群HLA多样性的局限，为建立更持久、更广泛的免疫保护提供理论依据和新的方向。

关键词： 3-(1,3-diarylallylidene) oxindoles   derivative   glycoprotein 130   interleukin-6   ovarian cancer   signal transducer and activator of transcription 3  

摘要： Background and PurposeDysregulation of the IL-6/glycoprotein 130(gp130)/STAT3 signalling axis is implicated in several human diseases, particularly cancer. Notably, gp130, a single transducer of this signalling axis, is a target for ovarian cancer treatment. However, data regarding small-molecule inhibitors of gp130 are lacking. Therefore, we aimed to identify a 3-(1,3-diarylallylidene)oxindole derivative that binds gp130 and reveal the anticancer mechanism acting on the IL-6/gp130/STAT3 pathway in ovarian *** ApproachWe synthesised 24 derivatives based on the scaffold of 3-(1,3-diarylallylidene)oxindole, and derivatives that inhibit IL-6 signalling were selected using HEK-Blue (TM) IL-6 cells. The binding of derivatives to gp130 was assessed using surface plasmon resonance. IA-0130, with a strong gp130-binding ability, was selected to observe its effect on the migration, invasion, cell cycle arrest and apoptosis of ovarian cancer cells in comparison to bazedoxifene, a known gp130-binding derivative. Additionally, we examined the mechanism underlying the tumour suppressive effect of IA-0130 in *** ResultsWe found that IA-0130 inhibited gp130/STAT3 phosphorylation in a concentration-dependent manner in ovarian cancer cell line and also in ovarian cancer-resistant cell line. By suppressing the expression of downstream target genes, IA-0130 inhibited cancer cell growth, metastasis, and invasion and induced apoptosis, exhibiting anticancer effects. In a mouse xenograft model of human ovarian cancer, oral administration of IA-0130 significantly delayed tumour growth. Conclusions and Implications IA-0130 inhibits tumour growth, migration and metastasis by inhibiting IL-6/gp130/STAT3 signalling in ovarian cancer by binding gp130. IA-0130 holds therapeutic potential for treating ovarian cancer as well as anticancer drug-resistant ovarian *** ResultsWe found that IA-0130 inhibited gp130/STAT3 phosphorylation in a concentration-dependent manner in

关键词： Asthma symptom subtypes   Healthcare disparities   Patient-reported outcome   Treatable traits   Unsupervised machine learning   ACQ-5   Asthma Control Questionnaire-5   AI   Artificial intelligence   BMI   Body mass index   FeNO   Fraction of exhaled nitric oxide   FEV   1   Percentage predicted forced expiratory volume in 1 s   GINA   Global Initiative for Asthma   ICS   Inhaled corticosteroid   IL   Interleukin   LABA   Long-acting β   2   agonist   LAMA   Long-acting muscarinic antagonist   LMICs   Low- and middle-income countries   PRO   Patient-reported outcome   SEACON   Subjective Evaluation of Asthma CONtrol by the physicians   T2   Type 2   UMAP   Uniform Manifold Approximation and Projection  

摘要： Background Heterogeneity of asthma requires a personalized therapeutic approach. However, objective measurements, such as spirometry and fraction of exhaled nitric oxide (FeNO) for implementing treatable traits approach, are limited in low- and middle-income countries and non-specialist settings. To implement precision medicine even with minimal resources, we developed an algorithm using unsupervised machine learning techniques that estimates key treatable traits (airflow limitation, type 2 [T2] inflammation, and frequent exacerbations) based on an asthma patient-reported outcome (PRO). Methods We applied hierarchical clustering and Uniform Manifold Approximation and Projection (UMAP) to Asthma Control Questionnaire (ACQ)-5 including five residual symptoms from two asthma cohorts (the discovery cohort with 1697 patients and validation cohort with 157 patients). Results We identified five symptom clusters, characterized by key treatable traits: Cluster 1, minimal asthma symptoms; Cluster 2, a little symptom, mild airflow limitation; Cluster 3, predominant shortness of breath and wheezes, airflow limitation; Cluster 4, predominant morning symptoms and nocturnal awakening, T2 inflammation; and Cluster 5, all symptoms severe, airflow limitation, T2 inflammation and frequent exacerbations. The UMAP projections of ACQ-5 (five-dimensional) to two-dimensions allowed to visualize datapoints and clusters, which visually revealed that patients with poorly-controlled asthma were divided into Clusters 3, 4 and 5. These results were externally validated in an independent cohort. Conclusions Based on asthma PRO data, the developed algorithm categorized asthma patients into five symptom-based subtypes that provide insights into key treatable traits. Our data-driven digital health approach will extend precision medicine of asthma to medical facilities even in resource-constrained settings.

关键词： Nephrotic syndrome   TNF-alpha   308 G/A   rs1800629   Asian   Meta-analysis  

摘要： IntroductionDespite its clinical significance, the precise pathogenesis of nephrotic syndrome (NS) remains elusive, with genetic factors and immune dysregulation implicated in disrupting glomerular filtration. Among these factors, TNF-alpha gene polymorphisms, such as the -308 G/A (rs1800629) polymorphism, have garnered attention in association studies with childhood NS. However, conflicting findings necessitate a comprehensive meta-analysis to delineate more precise *** literature was searched in PubMed, Web of Science, and Google Scholar (title search only) until September 15, 2024. Studies that determine the association of the rs1800629 among NS vs. controls were retrieved and synthesized to compute for the odds ratios and 95% confidence interval using Review Manager *** various genetic models, including allelic, co-dominant, dominant, and recessive models, significant associations were found between the rs1800629 polymorphism and NS susceptibility, favoring disease development in the presence of the variant allele. Based on geographic location and adjustment for factors like Hardy-Weinberg equilibrium and age groups, subgroup analyses reinforced these findings. Notably, the Asian subgroup exhibited stronger associations compared to *** present meta-analysis showed that the rs1800629 polymorphism is associated with NS susceptibility. However, despite the robustness of these results, further large-scale and prospective studies are warranted to validate these conclusions comprehensively.

关键词： biomarkers   cytokines   genetic polymorphisms   immune regulation   inflammation   interleukin-35   non-surgical periodontal therapy   periodontitis  

摘要： Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, () has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. This narrative review evaluates the role of in periodontal disease by exploring its local and systemic expression, response to non-surgical periodontal therapy (NSPT), and association with clinical disease severity. Additionally, current evidence regarding gene polymorphisms and their potential contribution to individual susceptibility and disease progression, as well as their relevance in related systemic conditions, is assessed. A comprehensive review and synthesis of recent clinical and experimental studies were conducted, focusing on levels in saliva, serum, and gingival crevicular fluid (GCF) among patients with healthy periodontium, gingivitis, and various stages of periodontitis, both before and after NSPT. Emphasis was placed on longitudinal studies evaluating dynamics in correlation with periodontal parameters, as well as genetic association studies investigating and gene polymorphisms. levels were generally found to be higher in healthy individuals and reduced in periodontitis patients, indicating a possible protective role in maintaining periodontal homeostasis. Following NSPT, levels significantly increased, corresponding with clinical improvement and reduced inflammatory burden. Genetic studies revealed variable associations between polymorphisms and susceptibility to periodontitis and related systemic conditions, although further research is needed for validation. appears to function as a modulator of immune resolution in periodontal disease, with potential utility as a non-invasive biomarker for disease activity and therapeutic response. Its upregulation during periodontal healing supp

关键词： CD1d-restricted NKT   central memory CD8(+) T   IL-15   Eomes  

摘要： The generation of memory CD8+T cells is essential for establishing protective T cellimmunity against pathogens and cancers. However, the cellular and molecular mech-anisms underlying memory CD8+T cell formation remain incompletely *** on specific pathogen-free (SPF) models, characterized by restricted microbialexposure, may limit our understanding of physiologically relevant immune memory de-velopment. This study reveals that CD1d(-)restricted NKT cells regulate central memory Tcell (TCM) generation exclusively in a microbe-rich ("dirty") environment. Under non-SPFhousing, CD1d+/-and Ja18(+)/(-)mice exhibited enhanced TCM formation compared toNKT-deficient controls (CD1d(-/-)/Ja18(-/-)), demonstrating that microbial experienceis required for NKT-mediated TCM regulation. Mechanistically, CD1d-restricted NKTcells increased IL-15R alpha expression on CD4+T cells in CD1d(+/)-mice, potentiating IL-15trans-presentation and thereby activating the IL-15/pSTAT5/Eomes axis critical for TCMmaintenance. Functional validation through adoptive transfer of CFSE-labeled OT-1 mem-ory cells revealed an NKT cell-dependent survival advantage in CD1d(+/-)hosts. Thisprovides direct evidence that microbiota-experienced niches shape immune memory. Col-lectively, these findings establish CD1d-restricted NKT cells as physiological regulatorsof TCM generation and suggest their potential utility as vaccine adjuvants to enhanceprotective immunity

关键词： C1q/TNF-related protein 1 (CTRP1)   chronic inflammation   kidney fibrosis   macrophage activation  

摘要： Chronic kidney disease (CKD), characterized by persistent inflammation and progressive renal fibrosis, remains a major therapeutic challenge due to an incomplete understanding of its pathogenesis. Since C1q/TNF-related protein 1 (CTRP1) plays a potential role in fibrosis and inflammation in other tissues, we investigated the role of CTRP1 in patients and mice with CKD. Here CTRP1 expression was increased in plasma and decreased in the kidneys of patients with CKD. Upregulation of renal CTRP1 with adeno-associated-CTRP1 was associated with decreased renal fibrosis, inflammation, macrophage accumulation, and activation in mice models. Mechanistically, CTRP1 abolished the expression of transforming growth factor beta 1 (TGF beta 1)-induced macrophage M2-associated genes and the transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). In addition, upregulation of CTRP1 could partly downregulate lipopolysaccharide (LPS)-stimulated expression of proinflammatory genes in vitro. Conditioned media from TGF beta 1-CTRP1-pretreated macrophages could less efficiently stimulate fibroblast activation compared with those from TGF beta 1-pretreated macrophages. Thus, our study reveals local CTRP1 as a potential regulator of chronic inflammation and kidney fibrosis through regulating macrophage activation. Taken together, these findings support renal CTRP1 as a novel therapeutic target for CKD.

摘要： Atopic dermatitis (AD) is a chronic inflammatory skin disorder caused by immune dysregulation that involves the release of various pro-inflammatory cytokines. Patients with AD frequently exhibit basophil infiltration in the affected skin. Although the role of the NLRP3 inflammasome in innate immune cells has been extensively studied, the contribution of the basophil inflammasome to the pathophysiology of AD remains to be elucidated. In this study, we demonstrated that IL-33 primes the NLRP3 inflammasome in basophils, leading to the production and release of mature IL-1 beta. Mechanistically, we showed that IL-33 stimulation induced pro-IL-1 beta and NLRP3 expression via the NF-kappa B and p38 MAPK pathways and that basophils released mature IL-1 beta through the canonical inflammasome activation pathway, which requires NLRP3, ASC, caspase-1, and gasdermin D (GSDMD). In an oxazolone (OXA)-induced AD mouse model, we found that basophils acted as key initiators of inflammation by producing IL-1 beta in the lesion, and that basophil depletion, genetic ablation of Nlrp3 or Il1b, or basophil-specific genetic ablation of Nlrp3 ameliorated ear swelling and neutrophil infiltration. Collectively, these findings establish basophils as a significant early source of NLRP3 inflammasome-driven IL-1 beta, contributing to the pathogenesis of AD. Targeting the IL-33/ST2L axis or NLRP3 inflammasome activation in basophils may offer a promising therapeutic strategy for managing AD.

摘要： Unresolved tissue damage is a common feature of Inflammatory Bowel Disease (IBD) that facilitates disease progression. Here, we showed that high animal fat diets (HFD), an environmental risk factor associated with IBD pathogenesis, suppress intestinal macrophage production of critical tissue repair responses after damage. This includes reduced IL-23 production, which drives downstream production of IL-22, which is needed for barrier repair. Indicating that dietary lipids interfere with responses to microbial molecules needed to induce barrier protective functions, we found oleic acid could directly suppress macrophage Il23a induction after lipopolysaccharide (LPS) treatment. Deleting the lipid transporter CD36 on macrophages restored the Il23a and Il22 response, reducing intestinal damage in HFD-fed DSS-treated mice. We found that CD36-mediated intracellular lipid accumulation, mainly oleic acid, in macrophages leads to peroxisome proliferator-activated receptor delta (PPAR delta) release of the transcriptional repressor protein B-cell lymphoma 6 (BCL6). BCL6 suppresses Il23a transcription in microbe-exposed macrophages. The studies suggest dietary lipid modulation of the macrophage PPAR delta/BCL6 transcriptional repressor complex is a key mechanism of fat-associated defects in intestinal damage repair and immune dysregulation. Overall, our findings provide new insights into dietary lipid contribution to intestinal disease progression and identify new potential therapeutic targets to decrease diet-associated risk for IBD.