课程文献中心 更多>>

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： Antiphospholipid antibodies   Inflammation   Interleukin-1 beta   MicroRNAs   Trophoblast   Toll-like receptor  

摘要： Women with antiphospholipid antibodies (aPL) are at high risk for pregnancy complications. In obstetric antiphospholipid syndrome (APS), aPL specific for beta2 glycoprotein I ((32GPI), target the placental trophoblast leading to inflammation. Studies from our group have shown that aPL trigger trophoblast cells to produce elevated inflammatory IL-1(3 and IL-8 via activation of Toll-like receptor (TLR) 4, and that downstream, IL-1(3 is mediated by uric acid-induced NLRP3 inflammasome activation, and IL-8 is mediated by a novel TLR8-activating microRNA (miR), miR-146a-3p. The objective of this study was to further explore the role of TLR7-and TLR8-activating miRs in the aPL-driven trophoblast chemokine and inflammasome response. Using the human first trimester trophoblast cell line, Sw.71, we found that aPL elevated miR-146a-3p expression but had no effect on levels of miR-21a, miR-29a or Let-7b. aPL-induced trophoblast IL-8 secretion was reduced by the TLR7 inhibitor, IRS661, and by the TLR8 inhibitor, CU-CPT9a, while aPL-induced uric acid, caspase-1 activity, and IL-1(3 secretion was reduced only by the TLR7 inhibitor. Over expression of miR-146a-3p using a specific miR mimic induced trophoblast IL-8 secretion in a TLR7-and TLR8-dependent manner, while miR-146a-3p induced trophoblast IL-1(3 secretion only via TLR7. This study highlights a role for TLR7/TLR8-activating miR-146a-3p as an intermediate signal that contributes to and modulates upstream TLR-driven trophoblast inflammatory responses, and adds to our knowledge of the molecular and innate immune mechanisms that underpin the pathogenesis of obstetric APS.

关键词： T cell receptor   Mouse sperm   Spermatogenesis   Soluble TCR   MHC   Soluble MHC  

摘要： Except from the myeloid in origin cells, ectopic expression of T-cell receptors (TCRs) was also detected in sperm and the female reproductive tract, which in conjunction with major histocompatibility complex (MHC) molecules suggested their involvement in mate choice. Following-up these observations and considering that MHC/TCR interactions could guide spermatozoa towards ovum, the present study aimed to delineate the presence of TCRs in sperm vis-& agrave;-vis cognate recognition and define such expression during spermatogenesis. Immunofluorescence experiments using fertile BALB/c males showed that despite the inbred origin of mice, all combinations of high (HI, >20 % expression) and low (LO, <5 % expression) TCR alpha beta and TCR gamma delta expression could be detected in equal distribution rates, followed by an inverse pattern of MHC expression. Samples TCR alpha beta Eta Iota did not express MHCI/II, but TCR alpha beta LO/TCR gamma delta HI samples showed increased expression of MHCII. High expression TCR alpha beta samples also expressed CD3e and CD4, but at lower than expected levels. In all cases, soluble TCRs and MHCs were detected by ELISA in the seminal fluid, where TCR alpha beta highly correlated with MHCI/II and TCR gamma delta with MHCI. Except from the classical alpha, beta, gamma and delta transcripts, RT-PCR experiments detected additional, not-yet identified products for alpha and gamma genes. Fluorescent microscope analysis identified TCR alpha beta and TCR gamma delta expression in spermatozoa tail. Immunohistology and cell dissociation of testis also detected TCR expression during spermatogenesis. Apart from un-folding novel structural, functional and regulatory features of TCRs in non-T cells, the results favor the involvement of TCRs in male reproduction and could serve as diagnostic markers in unexplained infertility.

关键词： Kidney Transplantation   HLA   Fairness   Kidney Exchange Programs (KEP)   Multi-Agent Kidney Exchange (MKEP)  

摘要： This paper presents a comprehensive review of the last two decades of research on Kidney Exchange Programs (KEPs), systematically categorizing and classifying key contributions to provide readers with a structured understanding of advancements in the field. The review highlights the evolution of KEP methodologies and lays the foundation for our contribution. We propose three mathematical models aimed at improving both the quantity and quality of kidney transplants. Model 1 maximizes the number of transplants by focusing on compatibility based on blood type and PRA, without additional constraints. Model 2 introduces a minimum Human Leukocyte Antigen (HLA) compatibility threshold to enhance transplant quality, though this leads to fewer matches. Model 3 extends the problem to a Multi-Agent Kidney Exchange Program (MKEP), pooling incompatible donor-recipient pairs across multiple agents, resulting in a higher number of successful transplants while ensuring fairness across agents. Sensitivity analyses demonstrate tradeoffs between transplant quantity and quality, with Model 3 striking the optimal balance by leveraging multi-agent collaboration to improve both the number and quality of transplants. These findings underscore the potential benefits of more integrated kidney exchange systems. (c) 2025 by the authors;licensee Growing Science, Canada

关键词： YB1   lipid metabolism   nonalcoholic fatty liver disease   NAFLD   inhibin Beta E   INHBE   TNF-beta signaling pathway   Y-box binding protein-1  

摘要： Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that has emerged as a significant public health concern. This study aimed to investigate the mechanisms by which Y-box binding protein-1 (YB1) knockdown influences lipid metabolism and oxidative stress in palmitic acid (PA)-induced NAFLD LO2 cells. The expression of YB1 was analyzed using the GSE89632 dataset from the Gene Expression Omnibus (GEO) database. RNA sequencing was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and proteinprotein interaction (PPI) network analyses to identify differentially expressed genes (DEGs). Quantitative Real-Time PCR (QRT-PCR), Western blotting, flow cytometry, and various biochemical assays were used to evaluate gene expression, lipid accumulation, and oxidative stress. Our results demonstrated that YB1 is highly expressed in NAFLD. RNA sequencing revealed 798 DEGs between the shCtrl and shYB1 groups, with 190 genes upregulated and 608 genes downregulated. Notably, we observed an increase in INHBE (Inhibin Beta E) expression, while EGR1, GDF15, NUPR1, and FOSB were decreased in NAFLD LO2 cells. YB1 knockdown, particularly when combined with INHBE suppression, significantly enhanced cell viability, improved lipid metabolism, and reduced reactive oxygen species (ROS) accumulation and malondialdehyde (MDA) content. The downstream mechanism was primarily associated with TNF-beta signaling. Specifically, we observed decreased levels of TGF-beta 1, p-Smad2, and p-Smad3 following YB1 and INHBE knockdown. Furthermore, INHBE overexpression reversed the beneficial effects induced by YB1 knockdown. In conclusion, YB1 knockdown improves lipid metabolism and reduces oxidative stress in NAFLD LO2 cells, largely through the INHBE/TNF-beta signaling pathway. These findings provide valuable insights into novel therapeutic strategies for managing NAFLD.

关键词： CD96/TACTILE   Uterine NK cell   CD96 splice forms   IL-15 and TGF(31   Flow Cytometry  

摘要： Uterine natural killer (uNK) cells are a tissue-specific subset of innate lymphocytes with unique functions including the engagement with placenta-derived extra-villous trophoblast (EVT) cells. While several receptorligand pairs of this interaction have been identified, many remain poorly characterized. Here, we investigated the expression and regulation of nectin-like receptor CD96/TACTILE on human uNK cells, which recognizes ligands expressed by EVT cells. Using flow cytometry, we analysed NK cells from menstrual blood and from first-and second-trimester decidua, alongside peripheral blood cells used as reference. We identified a predominant exon 4-lacking splice variant of CD96 on uNK cells and found that CD96 is part of a broader set of receptors associated with NK cell tissue-residency regulated by IL-15 and TGF(31. In vitro, IL-15 and canonical as well as non-canonical TGF(31 signalling upregulate CD96 surface expression. Finally, redirected cross-linking assays showed no major effect of CD96 engagement on degranulation in decidual NK (dNK) cells. Taken together, these findings reveal that human uNK cells adapt to an IL-15-and TGF(31-rich environment by shifting nectin-like receptor expression, with potential implications for dNK-EVT interactions during placentation.

关键词： Alarmin cytokines   Fibroblasts   Osteogenic signaling   RNA interference   Joint remodeling  

摘要： Objective: To investigate the pathogenic role of IL-33 in spondyloarthritis (SpA) by analyzing its expression in both murine and human joint tissues and functionally assessing its impact on fibroblasts. The study evaluated synovial and entheseal biopsies from patients with SpA to explore the potential contribution of IL-33 to joint inflammation and tissue remodeling. Methods: A spontaneous arthritis model (SpAD) in DBA/1 mice was used to assess IL-33 expression via histology, immunohistochemistry, transcriptomics, RT-qPCR, and western blot. Sacroiliac and tarsal biopsies from patients with SpA were also analyzed. Differential gene expression was checked, and pathway enrichment was performed using Ingenuity Pathway Analysis. Primary fibroblasts were isolated from the joints of the mice's front and rear limbs, transfected with siRNA targeting Il33, and evaluated by RT-qPCR and western blot for inflammatory (Tnf, Nfkb) and osteogenic (Wnt2, Bmp2) markers. Cell viability was assessed via MTT assay. Results: IL-33 expression was elevated in murine and human SpA joints, with strong cartilage and subchondral bone localization. Transcriptomic data indicated upregulation of IL-33 signaling and enrichment of proinflammatory and fibrotic pathways. Silencing of Il33 in fibroblasts significantly reduced IL-33 protein levels and decreased Tnf and Wnt2 expression at both mRNA and protein levels, while Bmp2 reduction was observed only at the transcript level. Conclusion: IL-33 contributes to joint inflammation and may regulate osteogenic pathways implicated in pathological bone formation. These findings support IL-33 as a potential dual-action therapeutic target in SpA.

关键词： Peptides   Artificial neural networks   HLA-I alleles   IFN-gamma   CD107a  

摘要： Toxoplasma gondii infects approximately 30% of the population, and there is currently no approved vaccine. Identifying immunogenic peptides with high affinity to different HLA molecules is a promising vaccine strategy. This study used an in silico approach using artificial neural networks to identify T. gondii peptides restricted to HLA-A*02, HLA-A*24, and HLA-B*35 alleles. Proteomes from seven T. gondii strains and transcriptomic data of overexpressed genes from T. gondii-RH in human PBMC were also used. Parasite protein sequences were analyzed with R 'Epitope Prediction' library. Peptide candidates were evaluated in the artificial neural networks based on the probabilities of output neurons (p > 0.5). The IFN-gamma responses in PBMC from T. gondii seronegative and seropositive individuals were evaluated by ELISpot. Peptides with higher IFN-gamma induction were evaluated to identify cytotoxic response in CD8+ T cells (CD107a). In silico analysis identified 36 peptides from T. gondii proteins with predicted affinity to HLA-A*02, A*24, and B*35 alleles. Experiments with PBMCs revealed that a peptide restricted to HLA-A02 (P1: FLFAWITYV) induced a significant increase in IFN-gamma-producing cells (p = 0.004). For HLA-A24, a peptide (P8: VFAFAFAFFLI) also induced a significant IFN-gamma response (p = 0.004), while for the HLA-B*35 allele, the P6 peptide (YPIAPSFAM) induced a response that differed significantly from the control (p = 0.05). These peptides induced also a significant percentage of central memory CD8 + T cells expressing the degranulation marker CD107a (p < 0.05). Finally, we identified three T. gondii peptides that induced IFN-gamma response, and a cytotoxic response measured by CD107a expression on CD45RAneg-CD8 cells. These peptides could be considered part of a multi-epitope vaccine against toxoplasmosis in humans.

关键词： Gout   CPPD   Crystal   Interleukin 6   Tocilizumab  

摘要： Gout and calcium pyrophosphate deposition disease (CPPD) are two highly prevalent causes of inflammatory arthritis, characterized by the pathological deposition of monosodium urate (MSU) and CPP crystals, respectively, in joint tissues. These crystals can induce an intense inflammatory response, known as crystal-induced inflammation, which involves innate immunity and is highly dependent of the activation of interleukin 13 (IL-1[3) following the recruitment ofthe NLRP3 inflammasome. In patients in whom first-line treatments (colchicine, prednisone, NSAIDs) are either ineffective or inappropriate, IL-1 inhibitors can be used to treat acute crystal-induced arthritis. However, some patients do not respond to these therapies, or experience adverse events. There is therefore a need for other treatments, particularly in CPPD, where the inflammation induced by CPP crystals can be chronic and affect elderly patients, making IL-1 inhibitors a less suitable option. IL-6, which is highly expressed during crystal-induced inflammation, is emerging as a promising therapeutic target in chronic CPP arthritis, with publications reporting the efficacy of tocilizumab in patients with inadequate response to other treatments, including anakinra, the most commonly used IL-1 inhibitor in this indication (off-label). These data require confirmation in randomized controlled trials. Other therapies, such as JAK inhibitors or NLRP3 inhibitors, may also be of interest in crystal-induced arthritis. (c) 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Societe Franc,aise de Rhumatologie. This is an open access article under the CC BY license (http://***/ licenses/by/4.0/).

关键词： Anti-cytokine autoantibodies   Phenocopy   Secondary immunodeficiency   Wound healing