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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： craniosynostosis   IL11RA gene   novel pathogenic variants  

摘要： BackgroundCraniosynostosis (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 *** 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 *** 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 *** 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.

关键词： HLA   HLA-DPB1*1783:01   novel allele   sequencing-based typing  

摘要： HLA-DPB1*1783:01 differs from HLA-DPB1*14:01:01:01 by one nucleotide substitution in codon 117 in exon 3.

关键词： IL37   IL18 signaling   Anti-inflammation   Homology modeling   Molecular dynamics simulations  

摘要： Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. However, none of the structures of IL37 complexes have been experimentally characterized. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations. We modeled all protein-protein complexes of IL37 using a range of methods from homology modeling to AlphaFold2 multimer predictions. Models that successfully recapitulated experimental features underwent further analysis through molecular dynamics simulations. As positive controls, binary and ternary complexes of IL18 from PDB were included for comparison. Several key findings emerged from the comparative analysis of IL37 and IL18 complexes. IL37 complexes exhibited higher mobility than the IL18 complexes. Simulations of the IL37-IL18Ra complex revealed altered receptor conformations capable of accommodating a dimeric IL37, with the N-terminal loop of IL37 contributing significantly to complex mobility. Additionally, the glycosyl chain on N297 of IL18Ra, which contours one edge of the cytokine binding surface, acted as a steric block against the N-terminal loop of IL37. Further, investigations into interactions between IL37 and IL18BP suggested that a binding mode homologous to IL18 was unstable for IL37, indicating an alternative binding mechanism. Altogether, this study accesses to the structure and dynamics of IL37 complexes, revealing the structural underpinnings of the IL37's modulatory effect on the IL18 signaling pathway.

关键词： HLA   HLA-DQA1   nanotype sequencing   novel allele   sequencing-based typing  

摘要： The novel allele HLA-DQA1*05:01:14 differs from HLA-DQA1*05:01:01:01 by one synonymous nucleotide substitution in exon 3.

关键词： rheumatoid arthritis   dementia   tumour necrosis factor   chronic inflammation   risk  

摘要： Objective Rheumatoid arthritis (RA) and Alzheimer's disease (AD) share characteristics of chronic inflammation and immune system dysregulation. RA patients are known to have an increased risk of dementia, yet studies on the association between tumour necrosis factor (TNF)-alpha blocker use and dementia risk in RA patients are lacking. This population-based cohort study aimed to investigate whether TNF-alpha blocker use is associated with a reduced risk of dementia in RA patients. Methods Using Taiwans' National Health Insurance Research Database, we identified RA patients treated with TNF-alpha blockers (etanercept, adalimumab and golimumab) and matched them 1:4 with RA patients receiving conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). A stratified Cox proportional hazard model was used to compare dementia risk between these groups. Results Among 3.987 RA patients using TNF-alpha blockers and 20,689 RA patients not using TNF-alpha blockers (comparison group), no significant difference in dementia risk was initially observed. However, upon further analysis stratified by TNF-alpha blocker exposure, RA patients with long-term (>180 cumulative defined daily dose [cDDD]) TNF-alpha blocker use had a significantly lower risk of dementia (adjusted hazard ratio [aHR]=0.578, 95% confidence interval [CI]=0.342-0.977), after adjusting for age, sex and comorbidities. Moreover, higher cumulative doses (>1036 cDDD) of TNF-alpha blockers were associated with a further reduced risk of dementia (aHR=0.387, 95% CI=0.188-0.793). Conclusion This nationwide cohort study suggests that long-term and higher cumulative doses of TNF-alpha blockers may be associated with a lower risk of dementia in patients with RA.

摘要： Background:Aptamers are RNA- or DNA-based oligomers with high protein-specific binding properties that have demonstrated effectiveness in targeting various proteins and treating diseases such as cancer. However, their application in regulating chronic respiratory diseases, such as chronic rhinosinusitis, is not well established. Methods:In this study, we used the anti-IL-4Rα aptamer (anti-IL-4Rα apt) to investigate its impact on IL-4 signalling and related T-helper 2 (Th2)-type inflammation in nasal polyp tissue. To achieve this, we treated nasal polyp tissue extracted from chronic rhinosinusitis with nasal polyps (CRSwNP) patients who had undergone polypectomy with the anti-IL-4Rα apt. Furthermore, to evaluate the effects of the anti-IL-4Rα apt on NP formation, we established an eosinophilic mouse model of CRSwNP to mimic the Th2 inflammatory pathogenesis observed in CRSwNP. Results:Interestingly, we observed that treatment with anti-IL-4Rα apt resulted in a significant reduction in IL-4-STAT6 signalling and Th2-mediated inflammation, as demonstrated by an ∼2-fold decrease in the levels of IL-4Rα, phosphorylated STAT6 (p-STAT6) and GATA3 in treated nasal polyp (NP) tissues compared to the untreated uncinate process (p<0.001). Notably, we observed that the administration of the anti-IL-4Rα apt effectively reduced NP formation and Th2-mediated inflammation, as shown by an ∼3-fold reduction in the percentages of IL-4Rα, p-STAT6 and GATA3 positive cells in the nasal tissues of this mouse model (p<0.001). Conclusion:Given that the anti-IL-4Rα apt demonstrated comparable efficacy to dupilumab - an anti-IL-4Rα therapy proven effective for CRSwNP - this research highlights the potential therapeutic efficacy of aptamers in managing chronic inflammatory conditions such as those seen in CRSwNP.

关键词： Proinflammatory   Mitophagy   mtDNA   STING   IFN   Oxidative phosphorylation  

摘要： Background & Aims: Autophagy plays an important role in liver regeneration. However, most studies are limited to hepatocytes, and the function and mechanism of macrophage autophagy in liver regeneration remain unclear. This study investigated the role of the essential autophagy gene encoding autophagy-related 16-like 1 (ATG16L1), which regulates the macrophage phenotype in liver regeneration. Methods: We generated FloxP-Atg16l1 (Atg16l1FL/FL), Lyz2-Cre Atg16l1 knockout (KO) (Atg16l1M-KO), and myeloid-specific Atg16l1-overexpression-knock-in (Atg16l1OE) mice. These mice were subjected to 70% partial hepatectomy to demonstrate the role of ATG16L1 in macrophages during liver regeneration. Results: ATG16L1 expression was significantly upregulated in macrophages during the early stages of liver regeneration. ATG16L1 deletion in macrophages substantially delayed liver regeneration in mice and caused a marked imbalance in Ly6Chi and Ly6Clo macrophage proportions in the liver. RNA-sequencing analysis revealed that, compared with macrophages isolated from Atg16l1FL/FL mice, those from Atg16l1M-KO mice exhibited significant downregulation of genes associated with oxidative phosphorylation and upregulation of proinflammatory gene expression. Mechanistically, ATG16L1 loss impaired mitophagy in macrophages, leading to the accumulation of mitochondrial damage and a metabolic shift that promoted proinflammatory macrophage polarization. ATG16L1 deficiency not only promoted macrophage mitochondrial (mt)DNA release and cyclic GMPAMP synthase-stimulator of interferon genes (STING) activation, but also suppressed STING degradation. Sustained STING hyperactivation and subsequent increased release of downstream interferons further contributed to the inhibition of liver regeneration. Notably, pharmacological activation or genetic overexpression of ATG16L1 significantly enhanced liver regeneration in mice. Conclusions: ATG16L1 has a pivotal role in liver regeneration by affecting the pheno

关键词： HLA-B   Indian   NGS   novel allele  

摘要： HLA-B*37:119 differs from HLA-B*37:01:01:01 by a single non-synonymous nucleotide change in exon 4.