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关键词： dapsone hypersensitivity syndrome   severe cutaneous adverse reactions   TNFR   TNF-alpha   VISTA  

摘要： BackgroundSevere cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life-threatening conditions with a mortality of 4%-20%. The clinical application of tumor necrosis factor-alpha (TNF-alpha) antagonist improves the outcome of some SCARs patients;however, this is complicated by the elusive and varied *** investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to *** clarify the precise process and optimize the therapy regimen of SCARs, we performed single-cell sequencing, in vitro functional and clinical analysis of patients with *** observed that TNF-alpha breaks drug-specific T-cell tolerance by inhibiting the expression of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA). Furthermore, TNF-alpha generated a positive feedback loop in the early phase of drug-specific T-cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF-alpha cytokine expression. In contrast, this pathway of TNF-alpha-VISTA signaling did not operate in memory effector T cells. Drug-specific memory effector T-cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF-alpha antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF-alpha antagonists significantly improved outcomes in SCARs *** findings defining feedback regulation of VISTA and Treg cells by TNF-alpha in different stages of the drug-specific T-cell response and, indicate that a Treg agonists, instead of TNF-alpha antagonists, could be used for treatment of patients with progressive SCARs.

摘要： Background: Several studies report that ashwagandha, a traditional Ayurvedic supplement, has anti-inflammatory properties. Type 2 (T2) asthma is characterized by eosinophilic airway inflammation. Objective: We hypothesized that allergen-induced eosinophilic airway inflammation in mice would be reduced following administration of Withaferin A (WFA), the primary active phytochemical in Ashwagandha. Materials and Methods: C57BL/6J mice were given 10 total intra-peritoneal injections of 2 mg/kg WFA or vehicle control, concurrent with 6 total intranasal administrations of 50 mu g house dust mite extract (HDM) or saline control over 2 weeks. Results: We observed that treatment with WFA reduced allergen-induced peribronchial inflammation and airway eosinophil counts compared to mice treated with controls. In addition, we observed that treatment with WFA reduced lung levels of interleukin-25 (IL-25) but increased lung gene expression levels of its co-receptor, Il17ra, in HDM-challenged mice compared to HDM-challenged mice that received the vehicle control. Conclusion: This study pinpoints a potential mechanism by which WFA modulates allergen-induced airway eosinophilia via the IL-25 signaling pathway. Future studies will investigate the effects of WFA administration on lung eosinophilia and IL-25 signaling in the context of chronic allergen-challenge.

摘要： The novel allele A*68:02:26 differs from A*68:02:01:01 by one nucleotide substitution in exon 8.

关键词： inflammatory bowel disease   IBD   Crohn's disease   TNF  

摘要： Background: As the use of anti-tumor necrosis factor-alpha (TNF alpha) therapies in Crohn disease (CD) is spread, the loss-of-response (LOR) to it is increasingly encountered. Discovering a pathological pathway and biomarkers that can predict LOR would assist in the management of patients with CD. In this article, we provide a comprehensive systematic review of studies assessing predictors of immunogenicity and loss-of-response to anti-TNF alpha drugs in patients with CD. Data sources: We performed a systematic review of PubMed to identify citations pertaining to predictors of immunogenicity and loss-of-response to anti-TNF alpha drugs in patients with CD through April 27, 2024, using a predefined string of keywords. Data extraction and quality assessment were performed independently by 2 reviewers. Results: A total of 18 eligible studies were included in the review. Four major groups of studies were identified: genetic factors, factors linked with colonic inflammation, serum and anthropological markers, and prevention of LOR. Promising predictors of LOR to infliximab or adalimumab include the carriage of HLA-DQA1*05, visceral adiposity, intestinal abundant presence of CD96, IL-17, and IL-23. Substantial heterogeneity was observed, and none of the markers had undergone formal validation. Specific limitations to acceptance of these factors included failure to use a standardized definition of LOR to anti-TNF alpha treatment, lack of specificity, and insufficient relevance to the pathogenesis of LOR. Conclusions: This review underlines the lack of well-defined studies and controlled trials investigating predictors of LOR to anti-TNF alpha therapies in CD. A research priority is the development of reliable and accurate biomarkers that can shed light on the pathogenesis of the implied LOR. These biomarkers, along with genetic factors, have the potential to enhance clinical management by aiding in patient stratification and monitoring.

关键词： HLA-DQB1   NGS   novel allele  

摘要： Five novel HLA-DQB1 alleles, HLA-DQB1*02:01:51, -DQB1*03:390:02, -DQB1*03:573, -DQB1*04:105 and -DQB1*05:03:39 in Russian donors.

关键词： Human leukocyte antigen   Micropolymorphism   Crystallography   HIV   Psoriasis  

摘要： Micropolymorphisms drastically shape the antigen presentation characteristics of human leukocyte antigen class I (HLA-I) molecules, with profound implications for immune responses and disease susceptibility. HLA-C*12:02 and HLA-C*12:03 are closely related HLA-I allotypes that differ by a single amino acid substitution (R97W) but exhibit distinct associations with disease. HLA-C*12:02 has been shown to provide protective effects against HIV infection, playing a crucial role in controlling viral replication and slowing disease progression, whereas HLAC*12:03 is associated with increased susceptibility to psoriasis. We determined the X-ray crystal structures of the two allotypes presenting MARELHPEY (MY9) and RAFPGLRYV (RV9). Peptide residues that function as anchors, as well as those accessible for T-cell antigen receptor (TCR) contact, were identified. Our results, combined with those of biochemical studies, demonstrated that the R97W variation alters the peptide-binding groove (PBG) volume and charge, leading to conformational and stability changes in pHLA-C*12 complexes and ultimately affecting peptide-binding preferences for the two HLA-C*12 allotypes. This research not only advances our understanding of the impact of HLA-I micropolymorphisms but also offers clues for the use of structure-guided therapeutics to interfere with peptide binding.

关键词： Foot rot   F.necrophorum   Skin explant   TNF-alpha   TNFR1   NF-kappa B  

摘要： Foot rot is a contagious disease caused by ***. It is responsible for economic losses in dairy farming. Studies on foot rot in dairy cows are focused on the isolation and identification of pathogens and treatment methods. Few studies have reported inflammatory changes in tissues and regulatory mechanisms following infection. Here, the effects of *** infection on the skin explants and skin fibroblasts between the toes of cattle were analyzed using histopathology and other techniques. *** infection increased the epidermal thickness and number of hair follicles and sebaceous glands. Other skin appendages exhibited varying degrees of necrosis, and a significant infiltration of inflammatory cells was noted in the interdigital skin explants. The expressions of pro-inflammatory cytokines (IL-1 beta and TNF-alpha) and key genes in the inflammatory signalling pathway (TNFR1 and NF-kappa B p65) were elevated. Treatment with the TNFR1 inhibitor CAY10500 reduced inflammatory cell infiltration and alleviated TNFR1 and p65 expression. An inflammatory cell model was established using different proportions of *** to infect BDF cells. *** infection significantly inhibited the proliferation and viability of BDF cells and enhanced the expression of TRADD, TRAF2, TNF-alpha, and IL-18. CAY10500 reduced the *** infection-induced inflammatory response and induced inflammatory responses in interdigital skin explants and BDF cells by inhibiting the TNF-alpha/TNFR1/NF-kappa B signaling pathway. In summary, these findings provide new insights into the mechanism of inflammatory responses in dairy cows with foot rot.

关键词： CD8+T cells   gastric cancer   IL36RN   prognosis   tumor microenvironment  

摘要： BackgroundGastric cancer (GC) remains a prevalent and lethal malignancy worldwide, underscoring the urgent need to identify novel therapeutic targets and elucidate the tumor microenvironment (TME) to enhance clinical ***36RN mRNA expression in GC tissues was analyzed using The Cancer Genome Atlas (TCGA) dataset. Bioinformatics approaches, cellular models, and clinical tissue microarrays were employed to investigate the functional role of IL36RN, its interactions within the TME, and its prognostic ***36RN expression was markedly upregulated in GC tissues and associated with unfavorable survival outcomes. Functional assays demonstrated that IL36RN silencing suppressed GC cell proliferation and invasion. Elevated IL36RN expression correlated with enhanced CD8+ T cell infiltration in the TME and served as an independent prognostic indicator in ***36RN represents a potential prognostic biomarker and therapeutic target in GC, offering novel avenues for precision oncology and immunotherapeutic intervention.