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摘要： The novel HLA-B*40:160:01:02 allele differs from HLA-B*40:160:01:01 at position 691 (G>T) in intron 2.

关键词： Hepatitis B Virus   CD8 T-cell pressure   sequence adaptation   HLA-associated mutational states (HAM)   viral load   HBeAg   whole-genome sequencing  

摘要： Background & Aims: Immune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T-cell epitopes has previously been described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear. Methods: Whole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for identification of HLA-associated mutational states (HAMs), the frequency and location of residues under CD8 T-cell selection pressure were determined and the levels of adaptation of individual isolates were quantified. Results: Using previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 Tcell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication levels. Conclusions: HBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T-cell-based therapies. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article

关键词： comparative effectiveness   multidisciplinary care   perianal fistula   setons  

摘要： Background and Aims: We aimed to assess the impact of setons on perianal fistula outcomes in patients with perianal fistulising Crohn's disease (PFCD) treated with anti-TNF therapy. Methods: We included patients treated with their first anti-TNF therapy for PFCD after undergoing a pelvic MRI between 2005 and 2022 from 6 North American centres. Our exposure was one or more setons at the time of anti-TNF therapy. Our primary outcome was major adverse fistula outcome (MAFO), a composite of repeat local surgical intervention, hospitalisation, or faecal diversion for PFCD, and our secondary outcome was fistula remission defined clinically. We used 1:1 cardinality matching and propensity score weighting to control for fistula severity based on centrally read MRIs, luminal characteristics, and concomitant therapies. Results: Our analysis included 221 patients: 81 with setons and 140 without setons. After cardinality matching, our cohorts were balanced (standardised difference < 0.1 for all covariates). Patients with setons had similar rates of MAFO (HR 1.23;95% CI, 0.68-2.21) and fistula remission at 6 months (OR, 0.81;95% CI, 0.41-1.59) and 12 months (OR, 0.63;95% CI, 0.31-1.27) compared to patients without setons. Our results remained stable when analysed by propensity score weighting and in a sensitivity analysis of patients who underwent an exam under anaesthesia. In patients with abscesses, there were lower rates of MAFO (HR, 0.49;95% CI, 0.19-1.25) but not statistically significant in patients with setons. Conclusions: In this multicentre, setons were not associated with improved fistula outcomes. Future prospective controlled studies are warranted.

关键词： EPA   DHA   Myogenic IL-6   Lipid metabolism   TRPV1/Ca2+   AMPK/STAT3  

摘要： Lipid metabolism disorder serve as a critical starting point for the development of chronic non-communicable diseases (NCDs). Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) are known for their lipid-lowering properties, but few studies have revealed their differences from the perspective of skeletal muscle endocrinology. Myogenic IL-6 has garnered significant attention for its role in energy distribution. The primary aim of this study was to investigate the effects and mechanisms of EPA and DHA on myogenic IL-6 and lipid metabolism disorders in mice, and to clarify the association between the alleviation of lipid metabolism disorders and myogenic IL-6 mediated by EPA/DHA. We found that EPA and DHA not only prevented high-fat diet- induced lipid metabolism disorders, but also up-regulated the expression of myogenic IL-6 by activating TRPV1/Ca2+ signaling in skeletal muscle. However, the lipid metabolism prevention effect mediated by EPA was weakened after knockout gene of myogenic IL-6, with its body weight and body fat increased and a large amounts of lipid deposited in the blood, liver, and adipocytes. Meanwhile, there no significantly differences of AMPK/STAT3 signaling in adipose tissue between groups after knockout gene of myogenic IL-6. Based on the results above, we concluded that EPA and DHA can stimulate the production of myogenic IL-6 through TRPV1/Ca2+ signaling in skeletal muscle. The prevention effect of lipid metabolism disorders by EPA, but not DHA, relies on myogenic IL-6, with the underlying mechanism may involving the enhancement of AMPK/STAT3 signaling mediated by myogenic IL-6 in adipose tissues. (c) 2024 Published by Elsevier Inc.

关键词： xMAP technology   CDC   Anti-HLA antibodies   Waiting list   Kidney transplant outcomes  

摘要： Background: Differences in sensitivity and specificity between the techniques used for the detection of anti-HLA antibodies before kidney transplantation (KT) can lead to contradictory results that influence patients' management. Our aim is to analyse whether the technique used, based on complement-mediated-cytotoxicity (CDC) or on microsphere fluorimetry (xMAP), conditions the waiting time until transplantation and its results. Methods: We performed a retrospective cohort study of the KT performed in our centre from 2006 to 2018 whose pre-transplant anti-HLA specificity determination and definition of prohibited antigens was performed by CDC (2006-2011) or by xMAP (2012-2018). Living donor KT recipients were excluded. The influence of each technique on the time on the waiting list and on the outcome of kidney transplantation was analysed, using as indicators the initial function of the graft, the rate of humoral rejection and graft survival. Results: During the period of the study, 622 patients were included (264 were studied by CDC and 358 by xMAP). Recipient and donor age was higher in the xMAP group (p < 0.001). Additionally, most sensitised patients were in the xMAP group (p < 0.001). However, they received a KT earlier. There were no differences in the rate of acute humoral rejection between groups. Nevertheless, graft survival was better in the xMAP group. Conclusions: The introduction of the xMAP technique in our centre has meant an improvement in terms of accessibility to transplantation and the initial management of the patient. However, it does not ameliorate the indicators of graft rejection.

关键词： Loteprednol etabonate   NLRP3 inflammasome   IL-1 beta   Pyroptosis   Sepsis   Colitis  

摘要： Excessive activation of the NLRP3 inflammasome leads to cellular inflammation and tissue damage. Finding an inhibitor of its activation is urgent need for NLRP3 inflammasome-associated inflammatory diseases. In this study, we identified Loteprednol etabonate (LE), a well-known anti-inflammatory drug for ocular conditions, as a potent inhibitor of NLRP3 inflammasome activation through screening an FDA-approved drug library. In cellular models, LE significantly reduced IL-1f) transcription, suppressed NLRP3 inflammasome activation, and finally inhibited the maturation and secretion of IL-1 beta and GSDMD-mediated pyroptosis. Mechanistic investigations showed that LE might inhibit IL-1f) transcription by blocking both NF-kappa B and AP-1 signaling pathways. Furthermore, in mouse models of NLRP3 inflammasome-associated inflammatory diseases, including LPSinduced sepsis and DSS-induced colitis, intraperitoneal injection of LE significantly suppressed inflammatory response and improved mice survival rate. Collectively, these findings identify LE as a novel inhibitor of NLRP3 inflammasome activation, offering a promising therapeutic strategy for the treatment of NLRP3 inflammasomeassociated inflammatory diseases.

关键词： antibody-mediated rejection   canakinumab   interleukin 6   kidney transplantation   tocilizumab  

摘要： Interleukin (IL)-6 is a major pro-inflammatory cytokine and central regulator of innate and adaptive immune responses. Clinical trials testing antibodies against IL-6 or its receptors have demonstrated its involvement in the pathogenesis of several autoimmune and inflammatory disorders and in the systemic inflammation and anemia associated to kidney failure and also in kidney allograft rejection. Additionally, the anti-IL-6 receptor antibody tocilizumab and the anti-IL-6 antibody clazakizumab have been studied for the treatment of naïve as well as resistant antibody-mediated kidney allograft rejection with mixed results in observational studies and early clinical development. Following promising results with a clazakizumab in a phase 2 placebo-controlled trial, a large phase 3 trial (IMAGINE) was terminated in 2024 for futility at interim analysis. Investigator-initiated clinical development continues in a smaller phase 3 trial testing tocilizumab (INTERCEPT). In this viewpoint article, we evaluate the pathophysiology of IL-6 in antibody-mediated kidney allograft rejection along with the current status of the clinical development of IL-6 targeting therapies for antibody-mediated kidney allograft rejection episodes within the wider frame of IL-6 targeting therapies in kidney failure that are considered the major causes of graft loss in kidney transplantation.

关键词： Human leukocyte antigen   Micropolymorphism   Crystallography  

摘要： Micropolymorphisms in human leukocyte antigen class I (HLA-I) molecules critically influence antigen presentation and immune recognition. Most studies have focused on variations within the peptide-binding groove (PBG), neglecting the potential impact of residues located outside this region. HLA-C*14:02 and HLA-C*14:03 differ only at position 21 (R21 and H21, respectively), which is situated outside the PBG, yet these two allotypes exhibit distinct clinical associations with HIV control in the context of KIR2DL2, an inhibitory killer cell immunoglobulin-like receptor that modulates natural killer (NK) cell activity. Here, we investigated the molecular mechanisms by which the R21H micropolymorphism shapes immune responses. Structural and biochemical analyses revealed that position 21 indirectly regulates the conformation of the B pocket within the PBG, significantly affecting HLA-C*14 stability and altering the composition of its peptide repertoire, while preserving core peptide motifs and recognition by KIR2DL2. Notably, the R21H variation is evolutionarily conserved across various HLA-I molecules and exhibits similar interactions with neighboring residues, suggesting a broadly conserved role in structural stability and immune regulation. These findings suggest that the stability differences between HLA-C*14 allotypes may influence their differential clinical associations, highlighting the previously underappreciated role of micropolymorphisms outside the PBG in modulating immune responses.

关键词： Osteoarthritis   polyphyllin I   TWIST1   chondrocytes   MMP-3   PPI  

摘要： Background Osteoarthritis (OA) is a chronic joint disease characterized by the degradation of articular cartilage. Polyphyllin I (PPI) has anti-inflammatory effects in many diseases. However, the mechanism of PPI in OA remains *** HC-a cells treated with IL-1 beta were identified by immunofluorescence staining and microscopic observation. The expression of collagen II and DAPI in HC-a cells was detected by immunofluorescence. The effects of gradient concentration of PPI on IL-1 beta-induced cell viability, apoptosis, senescence, and inflammatory factor release were detected by MTT, flow cytometry, SA-beta-Gal assay and ELISA, respectively. Expressions of apoptosis-related genes, extracellular matrix (ECM)-related genes, and TWIST1 were determined by qRT-PCR and western blot as needed. The above-mentioned experiments were conducted again after TWIST1 overexpression in IL-1 beta-induced *** IL-1 beta reduced the number of chondrocytes and the density of collagen II. PPI (0.25, 0.5, 1 mu mol/L) had no effect on cell viability, but it dose-dependently elevated the inhibition of cell viability regulated by IL-1 beta. The elevation of cell apoptosis, senescence and expression of IL-6 and TNF-alpha were suppressed by PPI in a dose-dependent manner. Additionally, PPI reduced the expression of cleaved caspase-3, bax, MMP-3, and MMP-13 and promoted the expression of collagen II. TWIST1 expression was diminished by PPI. TWIST1 overexpression reversed the above-mentioned effects of PPI on *** PPI suppressed apoptosis, senescence, inflammation, and ECM degradation of OA chondrocytes by downregulating the expression of TWIST1.

关键词： IL11RA gene   craniosynostosis   novel pathogenic variants  

摘要： BACKGROUND:Craniosynostosis (CS), a heterogeneous craniofacial disorder caused by premature fusion of cranial sutures, is sub-classified anatomically by suture involvement (sagittal, metopic, coronal, lambdoid) and phenotypically into isolated/non-syndromic forms or syndromic (CS with extracranial anomalies). Pathogenic variants in multiple genetic loci have been implicated in CS, with particular significance attributed to allelic variants in IL11RA (interleukin-11 receptor alpha subunit; OMIM#600939). Clinical observations of individuals with IL11RA mutations indicate syndromic CS, characterized by dental anomalies and Crouzon-like facial features. METHODS:Genetic analyses were carried out utilizing whole-exome sequencing, with subsequent validation through direct Sanger sequencing. IL11RA biallelic pathogenic variants were detected and further analyzed by multiple in silico prediction tools, including 3D protein modeling. RESULTS:Our cohort comprises six pediatric patients presenting with CS linked to biallelic pathogenic mutations in IL11RA, including two previously unreported variants (***218Argfs*140, ***132Ter). Three-dimensional protein structure modeling and molecular docking simulations demonstrated that four missense variants (***116Leu, ***126Gly, ***231Val, ***236Pro) disrupt hydrogen bond networks critical for maintaining the IL-11 receptor alpha subunit's tertiary structure, significantly reducing ligand-binding affinity to both interleukin-11 (IL-11) and gp130. CONCLUSION:This study describes the clinical phenotype of six children with craniosynostosis and reveals novel variants in the IL11RA gene, thereby broadening the genotypic spectrum associated with this gene. Given the scarcity of patients reported in the literature, a detailed examination of the specific clinical and molecular characteristics will benefit our understanding of craniosynostosis caused by IL11RA variants.