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关键词： MHC polymorphism   Evolution   Bioinformatics   Primates   Selective sweep  

摘要： T cells recognize peptides displayed on the surface of cells on MHC molecules. Genetic variation in MHC genes alters their peptide-binding repertoire and thus influences the potential immune response generated against pathogens. Both gorillas and chimpanzees show reduced diversity at their MHC class I A (MHC-A) locus compared to humans, which has been suggested to be the result of a pathogen-mediated selective sweep. More specifically, gorillas lack A3 lineage alleles while chimpanzees seem to have lost the A2 lineage. While previous studies showed this using phylogenetic analysis, here, we take an in silico functional approach and use the peptide-MHC binding prediction software NetMHCpan to examine the peptide-binding repertoires of common human, chimpanzee, and gorilla MHC-A molecules. We find that both gorillas and chimpanzees lack the A02 peptide binding specificity (supertype) despite gorillas being expected to have this specificity since they kept the A2 lineage. Additionally, we show that human MHC molecules with the A02 specificity bind fewer virus-derived peptides than other MHC molecules. We also do not find differential presentation of self-peptides by the A02 supertype, making the purpose of maintaining this specificity in high frequencies in the human population unclear. Taken together, we hypothesize that poor presentation of viral peptides by A02 supertype MHC molecules could have resulted in a selective sweep in chimpanzees and/or gorillas, though we could not identify a specific virus that may have caused this sweep.

关键词： ADA2 deficiency   Beh & ccedil   et's disease   Rheumatic disease   Children   HLA-B*51   Autoinflammatory  

摘要： Purpose Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease resulting from biallelic loss-of-function mutations in ADA2 gene. It has variable clinical manifestations, some of which can mimic Beh & ccedil;et's disease (BD). Herein, we present a family of three siblings diagnosed with DADA2, two of whom were initially misdiagnosed as BD based on clinical phenotype including positive human leukocyte antigen B51 (HLA-B*51). Methods Gene mutational analysis was performed by whole exome (WES) and Sanger sequencing. Results We reported two siblings presented with recurrent oral ulcers, fever, arthritis, and skin lesions, alongside elevated inflammatory markers and HLA-B*51 positivity, leading to an initial misdiagnosis of BD. Genetic testing later revealed a homozygous ADA2 variant (c.139G > A ***47Arg) in both siblings and their asymptomatic younger sister, confirming DADA2 diagnosis. Thereafter, we reviewed the literature to identify other patients misdiagnosed with BD but later found to have DADA2. This resulted in a cohort of 10 DADA2 patients, including our two reported siblings. The median time from symptoms onset to the final diagnosis of DADA2 was 7 years. All patients exhibited BD-like phenotype, except for uveitis, and 8 were HLA-B*51 positive, which likely contributed to the diagnostic confusion. Conclusion These findings highlight the broad clinical spectrum of DADA2, which can resemble BD, and suggest that HLA-B*51 positivity in DADA2 may further complicate diagnosis. Clinicians should maintain a high index of suspicion for DADA2 in early-onset BD-like cases, particularly without uveitis, or a family history of similar symptoms. Further studies are warranted to explore HLA-B*51 role in DADA2 phenotype.

关键词： WGA   IMDA   PCR-SSP   HLA ligands   Dengue patients  

摘要： BackgroundHigh-throughput DNA sequencing technologies have revolutionized genetic studies of populations and diseases. These methods provide deeper insights into gene structure and variation, offering more comprehensive immunogenetic data with stronger relevance to protein function and biological impact. However, the widespread adoption of high-resolution sequencing is hindered by factors such as cost and limited accessibility. Furthermore, successful implementation requires high-quality and sufficient quantities of genomic *** and resultsThis study addresses the challenges of limited DNA yields, a common issue in clinical samples, by employing whole-genome amplification (WGA) with isothermal multiple displacement amplification (IMDA). We investigated HLA ligands in 253 dengue samples with low DNA quantity. A multiplex PCR-SSP method was developed to determine HLA ligands in population, including HLA-C1, HLA-C2, HLA-A (Bw4), HLA-Bw4 (I80), HLA-Bw4 (T80), and HLA-A*11. The study successfully demonstrates the applicability of a multiplex PCR-SSP method for HLA genotyping in a large cohort of dengue patients. Our findings highlight the high prevalence of HLA-C1 (92.1%) and HLA-A*11:03 (78.3%) in dengue patients, providing valuable data for further investigations into the role of HLA polymorphisms in *** study demonstrates the utility of our approach for investigating HLA ligands in clinical samples with limited DNA. WGA-IMDA effectively overcomes the challenge of low DNA availability, making this approach suitable for resource-constrained settings. The multiplex PCR-SSP method provides a simple and cost-effective solution for immunogenetic studies.

关键词： IL-21   Inflammation   Lymphocytes   S. aureus   Septic arthritis   TGF-beta   Th17/Treg  

摘要： Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, na & iuml;ve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-beta in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-beta and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-beta 1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-kappa B, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-beta and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-beta and IL-21 could pr

关键词： Hepatitis C   HCV   Cellular immune response   CD8(+ )T response   HLA-A*02:01   Peptide microarray  

摘要： Several barriers for the development of an HCV vaccine still exist, including the genetic diversity of the virus, and the shortage of assessable models for in vitro and in vivo assays. Therefore, in this study, HCV epitope mapping was performed for 59 polyprotein sequences from 7 HCV genotypes. Around 2,880 peptides were considered epitopes for CD8+ T cells. The peptide induction of cytokines from Th1 and/or Th2 axes of the cellular immune response was assessed, indicating a tendency for Th2 axis. In vitro evaluation was performed using peptide microarray and a recombinant HLA-A*02:01 molecule. A total of 615 peptides of high reactivity to HLA-A*02:01 were identified, with predominance of leucine and tryptophan residues, highlighting their importance for TCR-epitope binding and CD8+ T activation. Finally, HCV-derived peptide patterns restricted to HLA-A2*02:01 observed in this study provide important information for the development of a multi-epitope-based pan-genotypic vaccine against the virus.

关键词： Sepsis   Acute respiratory distress syndrome (ARDS)   IL-27   Nrf2/HO1   Ferroptosis  

摘要： ObjectivesAcute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulated by macrophages. This study aimed to elucidate the effect of Recombinant Mouse IL-27 Protein on macrophage ferroptosis and polarization, as well as its impact on sepsis-induced *** cecal ligation and puncture (CLP)-induced sepsis model was established using wild-type (WT) or IL27R-/- mice. Then, the mice were randomly divided into 4 groups: a control group, a CLP group, an IL-27 + CLP combination group, and an IL-27, CLP, and Oltipraz combination group. RAW 264.7 cells and BMDMs were used to further determine the role and mechanism of IL-27 in *** vitro, IL-27 alone did not alter the expression of proteins linked to the ferroptosis pathway or macrophage polarization. Contrastingly, the combination of IL-27 with LPS further amplified LPS-induced alterations in the ferroptosis pathway, thereby promoting macrophage M1 polarization and inhibiting M2 polarization. Additionally, IL-27 + LPS increased ROS levels in macrophages. A sepsis-induced ARDS mouse model was then established via CLP. In vivo, IL-27 exacerbated CLP-induced lung injury in WT mice. Additionally, it decreased the expression levels of ferroptosis-related proteins (Nrf2, HO-1, GPX4) and increased those of Ptgs2 in the lung tissue of septic mice. Besides, GSH and SOD levels in lung tissue were also reduced. Moreover, IL-27 also promoted M1 polarization and inhibited M2 polarization in macrophages. In IL27R-/- mice, the effects of IL-27 were abrogated. Oltipraz inhibited IL-27-induced changes by up-regulating Nrf2 expression. Overall, this present study demonstrated that the combination of IL-27 and LPS-induced macrophage ferroptosis, promoted macrophage M1 polarization, and inhibited M2 polarization by inhibiting the Nrf2/HO-1 *** may alleviate ARDS-relat

关键词： rs641153   Complement   Evolution   Factor B   HLA   Primates   Complotype   MHC   Bf   C2   C4   Disease   Orangutan   Immunity   Chimpanzee auroimmunity  

摘要： BackgroundMajor Human Histocompatibility complex (MHC or HLA in humans) has been associated to autoimmune diseases. However, only statistical phenomenological and no pathogenetic description has been reached after decades. This shows that MHC single locus association studies are probably useless for HLA/diseases association. Extended HLA (class I and class II genes) haplotypes should also be studied conjointly with class III or complement alleles (complotypes). Complotypes in humans are defined as alleles belonging to C2, C4 and Bf (Factor B) genes/proteins (class III). Also, the placing of MHC class I and class II genes close together with complement genes from at least birds to humans shows existence of a strong selection to gather conjointly these loci that fight microbes, help self-maintenance and avoid autoimmunity. In this paper we aim to study Bf alleles in primates in order to rise again interest to study the role of Bf alleles together with other MHC genes in their physiopathology and *** (Pongo pygmaeus, Popy) cell lines RNA from 6 different individuals were retrotranscribed, PCR amplified, cloned and DNA sequenced in order to study Bf *** Bf allele identical to that found in chimpanzee (Patr-Bf*A01) and human (rs641153) was found in two of the six studied orangutans: Popy-Bf*A01 and Popy-Bf*A02. This polymorphism is placed in Factor B codon 32 that defines BF*S and Bf*F proteins in man and produce Leu instead of Arg (Bf*S) or Gln (Bf*F). In addition, each new orangutan allele present synonymous differences with each other at codon 25: Popy-Bf*A01 shows ACG while Popy-Bf*A02 bears ACA, both codifying for *** selection for about 15 million years (time gap of evolutionary appearance between orangutan and hominids) shows the importance of this particular allele conservation in immune and self defense in primates. The complotypes (Bf,C2 and C4 loci) alleles together with other MHC class I and Cass II loci alle

关键词： Asthma   Airway inflammation   Decline   Eosinophils   Lung Diseases  

摘要： Background Asthma is associated with accelerated rate of FEV1 decline. ObjectiveTo determine predictive factors associated with accelerated FEV1 decline in adult asthma and evaluate sputum cytokines as potential biomarkers for airflow decline. Methods We recruited 125 asthmatics evaluated at the asthma clinic of Li & egrave;ge and reevaluated them at least 5 years later. Clinical, functional and inflammatory characteristics were compared between patients with accelerated decline (FEV1 decline > 0.85% pred.y(-1)) and others. Predictive factors were highlighted with linear regression analysis. Sputum EGF, VEGF, FGF, IL5, IL8, TGF-beta, and IgE levels were measured in 58 of these patients at both visits by Human XL cytokine Luminex Performance assay and Elisa. Results Post-BD FEV1 decline was 0.06 +/- 2.44% pred.y-1 in the overall population. Median (IQR) time between visits was 66 (62 - 86) months. The multivariable analysis showed that an increase in blood eosinophils over time (Delta BEC) (Reg. Coef. (95%CI): 0.002 (0.001 to 0.004), p = 0.005)) and onset of asthma (0.04 (0.003 to 0.07), p = 0.036) were independently associated with FEV1 decline. IL8 levels measured at baseline were higher (499 (408-603) pg/ml, p = 0.0040) in patients with accelerated decline compared to others (143 (88-308) pg/ml). Conclusion In this study, we have confirmed that an increase in blood eosinophil counts over a follow-up of at least 5 years and later onset of asthma are associated with accelerated annual FEV1 decline. Moreover, high sputum IL8 levels could be a risk factor for accelerated decline in asthma patients.

关键词： 盐酸青藤碱   急性T淋巴细胞白血病   CEM细胞   细胞凋亡   RNA-seq测序   增殖抑制   工程化细胞  

摘要： 背景:盐酸青藤碱有抗多种肿瘤的作用,但目前尚不清楚盐酸青藤碱对急性T淋巴细胞白血病的作用。目的:探讨盐酸青藤碱对急性T淋巴细胞白血病CEM细胞的抑制作用。方法:应用不同浓度(0.5,1,2,4 mmol/L)盐酸青藤碱处理CEM细胞,CCK-8检测细胞增殖抑制率并计算IC50;倒置显微镜和吉姆萨染色观察CEM细胞形态变化;利用RNA-Seq测序分析差异基因表达并进行生物信息学分析。结合转录组测序结果,流式细胞术检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞凋亡率;Western blot检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞中Bcl-2、Bax、Caspase-9蛋白的表达。结果与结论:①盐酸青藤碱呈剂量和时间依赖性地抑制CEM细胞生长;②盐酸青藤碱干预后CEM细胞数量下降,核固缩;③RNA-seq测序筛出53个异常表达基因,基因本体分析主要富集在细胞过程、细胞解剖实体与粘连关系等,信号通路分析与肿瘤相关的是细胞凋亡;④盐酸青藤碱呈剂量依赖性地促进CEM细胞凋亡;⑤盐酸青藤碱上调CEM细胞中Bax、Caspase-9蛋白表达,下调Bcl-2蛋白表达。由此可见,盐酸青藤碱可诱导CEM细胞凋亡从而抑制细胞增殖,可能与其上调Bax和Caspase-9蛋白表达,以及下调Bcl-2蛋白表达有关。

关键词： Hydroxychloroquine   IgA nephropathy   network pharmacology   TNF   toll-like receptor signaling pathway  

摘要： Background IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the *** PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was *** 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine *** This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.