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关键词： interleukin-18   interleukin-18 receptor   molecular dynamics simulation   point mutagenesis   protein conformation   protein dynamics  

摘要： Engineered interleukin-18 (IL-18) has attracted interest as a cytokine-based treatment. However, knowledge-based mutagenesis of IL-18 has been reported for only a few regions of the protein structures, including binding sites I and II. When coupled with the binding region mutant (E6K), the non-binding residue of IL-18, Thr63 (T63), has been shown to increase the flexibility of the binding loop. Nevertheless, the function of Thr63 in conformational regulation is still unknown. Using homology modeling, molecular dynamics simulation, and structural analysis, we investigated the effects of Thr63 alteration coupling with E6K on conformational change pattern, binding loop flexibility, and the hydrogen bond network. The results indicate that the 63rd residue was significantly associated with hydrogen-bond relaxation at the core beta-barrel binding sites I and II Glu85-Ile100 loop. This result provided conformational and flexible effects to binding sites I and III by switching their binding loops and stabilizing the 63rd residue cavity. These findings may pave the way for the conceptualization of a new design for IL-18 proteins by modifying non-binding residues for structure-based drug development.

关键词： Primary Sjogren's syndrome   Autoimmune disease   Genetic   Epigenetic   HLA   Interferon   RNA  

摘要： Primary Sjogren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by a wide spectrum of glandular and extra-glandular features. Genetic and epigenetic factors play an important role in the disease susceptibility and phenotype. There are a multitude of genes that have been identified as implicated in the pathogenesis of pSS, both in HLA and extra-HLA regions with a strong contribution given by genes in interferon signalling pathways. Among the HLA alleles, the most consistent associations have been found with DR2 and DR3 alleles at the DRB1 locus. Moreover, several gene variants outside the MHC locus are in genes involved in NF-kappa B signalling, B- and T-cell function and methylation processes possibly responsible for lymphomagenesis. There is still a lack of knowledge on precise genetic patterns and prediction models of diseases, and data on pharmacogenetics is scarce. A comprehensive summary of the common genetic factors and an extensive analysis of novel epigenetic aspects is provided, together with a view on the relationships between novel therapeutic agents for pSS and genetic targets in signalling pathways, aiming at improving tailored treatment strategies in the view of a more personalized medicine.

关键词： leucoselect phytosome   TNF   CCL3   granzyme B   bronchoalveolar lavage   lung microenvironment   cell invasion  

摘要： Grape seed procyanidin extract (GSE) is widely used to promote cardiovascular health and has purported anti-inflammatory properties. Chronic inflammation in the lungs caused by environmental toxins such as tobacco smoking plays a pivotal role in lung cancer development. In a modified phase I lung cancer chemoprevention study conducted in heavy active and former smokers using leucoselect phytosome (LP), a standardized grape seed procyanidin extract complexed with soy phospholipids to enhance bioavailability, three months of LP treatment favorably modulated a variety of surrogate endpoint biomarkers, including markers of cell proliferation. In this correlative study, we further analyzed the effects of LP on cytochrome P450 3A4 (CYP3A4) activities by comparing the endogenous conversions of cortisol and cortisone to 6-beta-hydroxycortisol and 6-beta-hydroxycortisone, respectively, before and after LP treatment and the anti-inflammatory effects of LP in the lung microenvironment of these participants by comparing a profile of inflammatory cytokines and chemokines in matched pre- and post-treatment bronchoalveolar lavage (BAL) fluids. LP treatment did not significantly alter CYP3A4 activity, and three months of LP treatment significantly decreased tumor necrosis factor (TNF), C-C Motif Chemokine Ligand 3 (CCL3) and granzyme B in BAL fluids. Furthermore, post-LP-treatment BAL fluids significantly reduced migration/invasion of various human lung neoplastic cells in vitro. Our findings support the anti-inflammatory effects of GSE/LP in the lung microenvironment and its potential utility for reducing cancerizing forces, as well as driving forces for other common respiratory diseases such as chronic obstructive pulmonary disease and asthma, in the lungs of heavy former and active smokers.

关键词： HLA-DRB1/DQB1   Autoantibody   Microbiota   In silico   T1D  

摘要： This study aimed to investigate the prevalence of insulin autoantibody (IAA), glutamic acid decarboxylase antibody (GADA), and insulinoma-associated antigen-2 antibody (IA-2A) in type 1 diabetes (T1D) children based on the presence of predisposing HLA-II alleles. Additionally, to assess the sequence homology between autoantigens of islet cells and selected proteins derived from gut bacteria in terms of their binding capacities to HLA risk alleles, HLA-DRB1/DQB1 alleles were determined by PCR-SSOP in 111 T1D children (probands) along with 222 parents and 133 siblings. Autoantibodies were measured by ELISA, and in silico analysis was run as follows: protein extraction, homology and epitope prediction, peptide alignment, and HLA-peptide docking. Higher significant frequencies of DRB1*03:01, DQB1*02:01, and DQB1*03:02 alleles and DRB1*03:01 similar to DQB1*02:01 haplotype and lower frequencies of DRB1*11:01, DRB1*14:01, and DQB1*03:01 alleles were found in probands compared to parents and siblings. DRB1*11:01 similar to DQB1*03:01, DRB1*14:01 similar to DQB1*05:03, and DRB1*15:01-DQB1*06:02 haplotypes were significantly less frequent in the probands compared to parents. Out of 111 probands, 21 were seronegative, 90 tested positive for one autoantibody, and 15 showed the concurrent presence of three autoantibodies. Logistic regression analysis revealed that DRB1*04 similar to DQB1*03:02 haplotype was associated with the induction of GADA and IA-2A, while DRB1*11:01 similar to DQB1*03:01 was associated with seronegativity. Epitopes derived from GAD and gut bacteria showed strong binding capacities to HLA risk alleles. Due to the sequence similarities between gut bacteria-derived proteins and islet cell autoantigens and their potential for binding to HLA risk alleles, dysbiosis of gut microbiota can be considered another risk factor for the development of T1D, especially in genetically susceptible individuals.

关键词： a novel allele   HLA-A   sequence-based typing  

摘要： HLA-A*02:889 differs from HLA-A*02:01:01:01 by one nucleotide exchange at position 506(C>G) with an amino exchange.

关键词： Immunopeptidomics   Mass spectrometry   Machine learning   Aliphatic index  

摘要： Accurately identifying neoantigens is crucial for developing effective cancer vaccines and improving tumor immunotherapy. Mass spectrometry-based immunopeptidomics has emerged as a promising approach to identifying human leukocyte antigen (HLA) peptides presented on the surface of cancer cells, but false-positive identifications remain a significant challenge. In this study, liquid chromatography-tandem mass spectrometry-based proteomics and next-generation sequencing were utilized to identify HLA-presenting neoantigenic peptides resulting from non-synonymous single nucleotide variations in tumor tissues from 18 patients with renal cell carcinoma or pancreatic cancer. Machine learning was utilized to evaluate Mascot identifications through the prediction of MS/MS spectral consistency, and four descriptors for each candidate sequence: the max Mascot ion score, predicted HLA binding affinity, aliphatic index and retention time deviation, were selected as important features in filtering out identifications with inadequate fragmentation consistency. This suggests that incorporating rescoring filters based on peptide physicochemical characteristics could enhance the identification rate of MS-based immunopeptidomics compared to the traditional Mascot approach predominantly used for proteomics, indicating the potential for optimizing neoantigen identification pipelines as well as clinical applications.

关键词： HLA-DRB4*01:03:01:21   novel allele   third-generation sequencing  

摘要： HLA-DRB4*01:03:01:21 differs from DRB4*01:03:01:11 by two nucleotide changes in intron 1 and intron 2.

关键词： Inflammatory bowel disease   Live vaccines   Anti-TNF therapy   Pregnancy   Breastfeeding  

摘要： Background: Anti-TNF are usually maintained during pregnancy in patients with inflammatory bowel disease (IBD) but safety is still a concern for them. Aims: To provide data on management of anti-TNF agents during pregnancy, safety of live vaccines (BCGMMR-rotavirus) and breastfeeding in newborns and dedicated information delivered to IBD women. Methods: We performed an observational study in 25 centers from 2016 to 2018. We administered questionnaires to women with IBD receiving anti-TNF during pregnancy with newborn follow-up >= one year. Results: Of 153 patients, 52 % maintained anti-TNF during the third trimester. Anti-TNF was shortly resumed in 79 % (58/73) after delivery. The rate of breastfeeding was 44 % (68/153) without any complication;38 % of the mothers denied to breastfeed based on physician's advice. 26 % (34/129) of the newborns received live vaccines before 6 months-old (BCG:30 %;MMR:63 %;Rotavirus:8 %) and only 3 complications occurred (local BCGitis = 1, fever = 2). Information concerning anti-TNF during pregnancy/post-partum was delivered to 92 % of the patients, mainly by a gastroenterologist (97 %) who discussed with the ob- stetrician or the paediatrician in only 48 % , 25 %. Conclusion: In IBD patients, maintaining anti-TNF during pregnancy and breastfeeding is safe. Accidental live vaccines before 6 months did not lead to significant adverse events. The communication about these questions remains to improve. (c) 2024 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

关键词： A*02:01:222   B*07:02:104   C*07:02:156   DQB1*06:03:51   new HLA allele   NGS  

摘要： Four novel HLA alleles HLA-A*02:01:222, -B*07:02:104, -C*07:02:156 and -DQB1*06:03:51 alleles detected during routine next generation sequencing.

关键词： cancer therapy   cholesterol   immunotherapy   MHC   PD-L1   platycodin D  

摘要： Most tumors are resistant to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors, which may be due to impaired antigen presentation resulting from the downregulation of major histocompatibility complex class I (MHC-I) expression on tumor cells. We observed that platycodin D (PD), polygalacin D, and platycodin D2, which are plant-derived triterpenoid saponins, significantly reduced PD-L1 levels. RNA sequencing and the PharmMapper database analysis identified liver X receptor beta (LXR-beta) as a potential PD target. Further studies showed that PD reduces PD-L1 levels by binding to LXR-beta and inhibiting LXR-beta activity. Coadministration of PD and nintedanib, known to upregulate MHC-I expression, enhanced tumor recognition and killing by T cells. This study provides new insights into PD applications and mechanisms.